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SMARCA2 and SMARCA4 are the mutually exclusive catalytic subunits of the mammalian Switch/Sucrose Non-Fermentable (SWI/SNF) chromatin remodeling complex, and have recently been considered as attractive synthetic lethal targets for PROTAC-based cancer therapy. However, the potential off-tissue toxicity towards normal tissues remains a concern. Here, we optimize a GSH-inducible SMARCA2/4-based PROTAC precursor with selective antitumor activity towards lung cancer cells and negligible cytotoxicity towards normal cells in both in vitro and in vivo studies. The precursor is not bioactive or cytotoxic, but preferentially responds to endogenous GSH in GSH-rich lung cancer cells, releasing active PROTAC to degrade SMARCA2/4 via PROTAC-mediated proteasome pathway. Subsequent xenograft model study reveals that selective SMARCA2/4 degradation in lung tumors triggers DNA damage and apoptosis, which significantly inhibits lung cancer cell proliferation without obvious adverse events towards normal tissues. This study exemplifies the targeted degradation of SMARCA2/4 in lung cancer cells by the GSH-responsive PROTAC precursor, highlighting its potential as an encouraging cancer therapeutic strategy., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Masson SAS. All rights reserved.)

Purpose: The role of dual-specificity phosphatase-5 (DUSP5) in BRAF-mutant thyroid cancers remains unclear. The aims of this study are to investigate the role of DUSP5 in BRAF-mutant thyroid cancer cells, explore its value in the diagnosis and evaluate therapeutic potential of targeting DUSP5 combined with sorafenib for BRAF-mutant thyroid cancer patients., Methods: The role of DUSP5 in thyroid cancer cells was determined by a series of in vitro and in vivo experiments. Underlying mechanisms were explored by western blotting analysis. The diagnostic value of combination detection of DUSP5 expression and BRAF V600E mutation was evaluated using ROC curve., Results: Knocking down DUSP5 in BRAF-mutant thyroid cancer cells significantly inhibited colony formation, cell migration and invasion, meanwhile, induced cell cycle arrest and cell apoptosis. Moreover, inhibition of DUSP5 improved the anti-tumor efficacy of sorafenib both in vitro and in vivo. Besides, combination detection of DUSP5 expression and BRAF V600E mutation showed much more accuracy in preoperative diagnosis of thyroid cancer., Conclusions: Our data demonstrate an oncogenic role of DUSP5 in BRAF-mutant thyroid cancer cells, and combined analysis of its expression and BRAF V600E mutation can accurately diagnose thyroid cancer. In addition, inhibition of DUSP5 improves the response of BRAF-mutant thyroid cancer cells to sorafenib., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Four new monoterpene rhamnosides, graphiumisides A-D (1-4), along with four known steroid compounds (5-8) were isolated from the fermentation extract of animal-derived endophytic fungus, Graphium sp. GD-11. The chemical structures of all compounds were elucidated using 1D and 2D NMR, HRESIMS spectroscopic analyses, and other spectroscopic methods. Compounds 1-4 exhibit a distinctive structure connected by one p-menthane type monoterpene and one L-rhamnose. This is the first report of monoterpene glycosides from Graphium sp. All compounds (1-8) were tested for cytotoxic activities against four cancer cell lines (HepG2, SMMC7721, SW480, and A549), and only compound 1 showed weak anti-tumor activity against SMMC7721 cells., (© 2024 Wiley-VHCA AG, Zurich, Switzerland.)

Photopharmacology is an emerging approach for achieving light-controlled drug activity. Herein, we design and synthesize a novel series of photoswitchable PI3K inhibitors by replacing a sulfonamide moiety with an azo group in a 4-methylquinazoline-based scaffold. Through structure-activity relationship studies, compound 6g is identified to be effectively switched between its trans - and cis -configuration under irradiation with proper wavelengths. Molecular docking studies show the cis -isomer of 6g is favorable to bind to the PI3K target, supporting compound 6g in the PSS 365 ( cis -isomer enriched) was more potent than that in the PSS dark ( trans -isomer dominated) in PI3K enzymatic assay, cell antiproliferative assay, Western blotting analysis on PI3K downstream effectors, cell cycle analysis, colony formation assay, and wound-healing assay. Relative to the cis -isomer, the trans -isomer is more metabolically stable and shows good pharmacokinetic properties in mice. Moreover, compound 6g inhibits tumor growth in nude mice and a zebrafish HGC-27 xenograft model.

The ancient anti-alcohol drug disulfiram (DSF) has gained widespread attention for its highly effective anti-tumor effects in cancer treatment. Our previous studies have developed liposome of Cu (DDC) 2 to overcome the limitations, like the poor water solubility. However, Cu (DDC) 2 liposomes still have shown difficulties in severe hemolytic reactions at high doses and systemic toxicity, which have limited their clinical use. Therefore, this study aims to exploratively investigate the feasibility of using DSF or DDC in combination also can chelate Zn 2+ to form zinc diethyldithiocarbamate (Zn (DDC) 2 ). Furthermore, this study prepared stable and homogeneous Zn (DDC) 2 liposomes, which were able to be released in the tumor microenvironment (TME). The released Zn (DDC) 2 was converted to Cu (DDC) 2 with the help of endogenous Cu 2+ -switch enriched in the TME, which has a higher stability constant compared with Zn (DDC) 2 . In other words, the Cu 2+ -switch is activated at the tumor site, completing the conversion of the less cytotoxic Zn (DDC) 2 to the more cytotoxic Cu (DDC) 2 for effective tumor therapy so that the Zn (DDC) 2 liposomes in vivo achieved the comparable therapeutic efficacy and provided a safer alternative to Cu (DDC) 2 liposomes in cancer therapy., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

Simultaneous inhibition of PI3K and HDAC has shown promise for treating various cancers, leading to discovery and development of their dual inhibitors as novel anticancer agents. Herein, we disclose a new series of PI3K/HDAC dual inhibitors bearing a benzamide moiety as the pharmacophore of HDAC inhibition. Based on systematic structure-activity relationship study, compounds 36 and 51 featuring an alkyl and benzoyl linker respectively were identified with favorable potencies against both PI3K and HDAC. In cellular assays, compounds 36 and 51 showed significantly enhanced antiproliferative activities against various cancer cell lines relative to single-target inhibitors. Furthermore, western blotting analysis shows compounds 36 and 51 suppressed AKT phosphorylation and increased H3 acetylation in MV4-11 cells, while flow cytometry analysis reveals both compounds dose-dependently induced cell cycle arrest and cell apoptosis. Supported by pharmacokinetic studies, compounds 36 and 51 were subjected to the in vivo evaluation in a MV4-11 xenograft model, demonstrating significant and dose-dependent anticancer efficacies. Overall, this work provides a promising approach for the treatment of AML by simultaneously inhibiting PI3K and HDAC with a dual inhibitor., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Masson SAS. All rights reserved.)

PARP-1/2 inhibitors have become an important therapeutic strategy for the treatment of HR-deficient tumors. However, discovery of new inhibitors with an improved and distinct pharmacological file still need enormous explorations. Herein, a series of novel highly potent PARP-1/2 inhibitors bearing an N -substituted piperazinone moiety were achieved. In particular, Cpd36 was identified as a distinct PARP inhibitor, showing remarkable enzymatic activity not only toward PARP-1 (IC 50 = 0.94 nM) and PARP-2 (IC 50 = 0.87 nM) but also toward PARP-7 (IC 50 = 0.21 nM), as well as high selectivity over other PARP isoforms. Furthermore, Cpd36 was orally bioavailable and significantly repressed the tumor growth in both breast cancer and prostate cancer xenograft model. The crystal structures of Cpd36 within PARP-1 and PARP-2 together with the predicted binding mode within PARP-7 revealed its binding features and provided insightful information for further developing highly potent and selective PARP-1 and/or PARP-7 inhibitors.

Chemodynamic therapy (CDT), a novel therapeutic approach based on Fenton (Fenton-like) reaction, has been widely employed for tumor therapy. This approach utilizes Fe, Cu, or other metal ions (Mn, Zn, Co, or Mo) to react with the excess hydrogen peroxide (H 2 O 2 ) in tumor microenvironments (TME), and form highly cytotoxic hydroxyl radical (˙OH) to kill cancer cells. Recently, nanoscale metal-organic frameworks (nMOFs) have attracted considerable attention as promising CDT agents with the rapid development of cancer CDT. This review focuses on summarizing the latest advances (2020-2022) on the design of nMOFs as nanomedicine for CDT or combination therapy of CDT and other therapies. The future development and challenges of CDT are also proposed based on recent progress. Our group hopes that this review will enlighten the research and development of nMOFs for CDT.

Targeting the colchicine binding site on tubulin is a promising strategy to develop cancer therapeutics. Herein, we describe our systematic structure-activity relationship studies of benzamide derivatives that lead to an identification of a potent and orally active tubulin inhibitor 48 , which occupied all three zones of the colchicine binding site in the X-ray co-crystal structure, inhibited tubulin polymerization, promoted mitotic blockade and apoptosis, and exhibited significant antiproliferative activities against various cancer cell lines. Compound 48 demonstrated favorable pharmacokinetic profiles, robust in vivo antitumor efficacies, and acceptable safety profiles. Furthermore, 48 overcame drug resistance in the paclitaxel-resistant A549 xenograft model. Collectively, 48 has been advanced into further preclinical evaluation for the development of next-generation microtubule-targeting drugs.

Hedgehog signal channel, a channel that plays a role in the occurrence and development of a variety of cancers. We introduce the composition and mechanism of Hedgehog signal channel, and the anti-tumor mechanism. A series of derivatives were designed and synthesized with the Hedgehog signal channel inhibitor Itraconazole in clinical phase II as the precursor. Compared with the other inhibitors, Itraconazole has a weaker inhibitory effect on Hedgehog, and there are few studies on improving the anti proliferation ability of Itraconazole on cells. Therefore, using Itraconazole as the lead, we obtained a series of derivatives that can effectively inhibit Hedgehog channels. Compared with Itraconazole, compounds 12g and 12n had stronger inhibitory effects in A549 cells., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Background: Chemotherapy-induced peripheral neuropathy (CIPN) is a common and understudied consequence of taxane chemotherapy for breast cancer treatment. CIPN symptoms include numbness combined with tingling sensations, persistent shooting, stabbing, or burning pain even in the absence of painful stimuli, lower extremity muscle weakness, and impaired balance. CIPN symptoms often persist for a long time after completion of chemotherapy, causing significant loss of functional abilities and increased risk of falls. Persistent CIPN caused by taxanes represents a therapeutic challenge due to the limited treatment options. Resistance exercise has shown promising results; however, the effect of exercise on CIPN remains understudied. This study aims to assess the effects of exercise on gait, balance, and lower extremity muscle strength after a 16-week home-based exercise program compared to an educational attention control condition., Methods: A sample of 312 women who completed taxane-based chemotherapy for breast cancer and have symptomatic neuropathy is recruited from a community-dwelling sample. Participants are randomized to either a 16-week Home-Based Physical Activity Intervention or an Educational Attention control group. The home-based intervention protocol consists of targeted lower extremity stretches, followed by 10 min each of gait/balance and 10 min of resistive training accessed by hyperlink or DVD. An Exercise Diary records quantitative exercise data. The gait assessment includes temporospatial parameters and lower extremity joint angles using APDM motion sensors. Participants' balance is assessed using the Sensory Organization Test (SOT) performed using a NeuroCom Balance Master. Isometric strength of hip, knee, and ankle flexor and extensor muscles is assessed using an isokinetic dynamometer, Biodex BX Advantage. In addition, we assess neuropathy symptoms using the FACT-Taxane Additional Concerns Subscale and nerve conduction velocity of the sural and peroneal nerve action potentials. Outcomes are assessed at baseline (prior to randomization) and 16 weeks., Discussion: There are currently no evidence-based interventions that address the functional declines associated with CIPN. If successful, this program is simple and easy to implement in the standard of care for individuals with CIPN. Gait and balance training have the potential to reduce physical dysfunction associated with CIPN and reduce the burden of disease in cancer survivors., Trial Registration: ClinicalTrials.gov NCT04621721 . Registered on August 3, 2020. ClincialTrials.gov is a primary registry of the World Health Organization International Clinical Trials Registry Platform (WHO ICTEP) network and includes all items from the WHO Trial Registration data set in Trial registration., (© 2022. The Author(s).)

Cisplatin is a widely used anticancer drug for various solid tumors. However, the serious adverse effects caused by systemic distribution limit its wide use. In this study, we intend to use biocompatible materials polyethyleneimine (PEI) and poly(L-glutamic acid)-g-methoxy poly(ethylene glycol) (PLG-g-PEG) to construct nanoparticles to enhance the efficacy of cisplatin and reduce its side effects. The micelle-like nanoparticles were fabricated by a simple two-step method, with a core consisting of PEI and cisplatin and a PLG-g-mPEG coating layer. The obtained nanoparticles have a small particle size (41.79 nm) and high drug loading (16.43%). The coated nanoparticles (NP-II) strengthened the structure of PEI and cisplatin complex (NP-I) and slowed the drug release for less than 20% at pH 7.4 PBS in 24 h. Therefore, it could effectively inhibit the binding of free drug and plasma proteins to achieve the long circulation, and the bioavailability could be increased to about 600% and 285% of cisplatin solution and NP-I respectively. Besides, the cellular uptake of NP-II was enhanced in the acidic tumor microenvironment due to the detachment of coating layer and the increase of positive zeta potential of nanoparticles, which was benefit to reduce the side effect of cisplatin to normal cells. In vivo pharmacodynamic experiments also showed that NP-II improved the efficacy and reduced side effects compared to the cisplatin solution. In conclusion, the two-step fabricating micelle-like nanoparticles with the improved therapeutic efficiency and reduced side effects show great potential for cancer chemotherapy., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Multiple myeloma (MM) ranks second in malignant hematopoietic cancers, and the most common anti-MM drugs easily generate resistance. CDK4/6 have been validated to play determinant roles in MM, but no remarkable progress has been obtained from clinical trials of CDK4/6 inhibitors for MM. To discover novel CDK6 inhibitors with better potency and high druggability, structure-based virtual screening was conducted to identify compound 10. Further chemical optimization afforded a better derivative, compound 32, which exhibited strong inhibition of CDK4/6 and showed high selectivity over 360+ kinases, including homologous CDKs. The in vivo evaluation demonstrated that compound 32 possessed low toxicity (LD 50  > 10,000 mg/kg), favorable bioavailability (F% = 51%), high metabolic stability (t 1/2  > 24 h) and strong anti-MM potency. In summary, we discovered a novel CDK4/6 inhibitor bearing favorable drug-like properties and offered a great candidate for MM preclinical studies., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 Elsevier Masson SAS. All rights reserved.)

Nowadays, the simultaneous inhibition of two or more pathways plays an increasingly important role in cancer treatment due to the complex and diverse pathogenesis of cancer, and the combination of the cyclin-dependent kinase 6 (CDK6) inhibitor and PIM1 inhibitor was found to generate synergistic effects in acute myeloid leukemia (AML) treatment. Therefore, we discovered a novel lead 1 targeting CDK6/PIM1 via pharmacophore-based and structure-based virtual screening, synthesized five different series of new derivates, and obtained a potent and balanced dual CDK6/PIM1 inhibitor 51 , which showed high kinase selectivity. Meanwhile, 51 displayed an excellent safety profile and great pharmacokinetic properties. Furthermore, 51 displayed stronger potency in reducing the burden of AML than palbociclib and SMI-4a in vivo . In summary, we offered a new direction for AML treatment and provided a great lead compound for AML preclinical studies.

Increasing evidence shows that the CXC chemokine receptor 2 (CXCR2) signaling pathway is essentially implicated in the recruitment of myeloid-derived suppressor cells (MDSCs) to the tumor microenvironment and leads to MDSC-mediated immune suppression. Therefore, CXCR2 has recently emerged as a promising drug target for cancer immunotherapy. In this paper, benzocyclic sulfone derivatives were designed as potent CXCR2 antagonists. Structure-activity relationship studies resulted in two lead compounds 9b and 11h , which demonstrated double-digit nanomolar potencies against CXCR2 and significantly inhibited neutrophil infiltration into the air pouch in an in vivo setting. More importantly, 9b and 11h dose-dependently inhibited the tumor growth through oral administration in the Pan02 mouse model. Further cytometry and immunohistochemical analyses revealed that 9b and 11h could reduce the infiltration of neutrophils and MDSCs and enhance the infiltration of CD3 + T lymphocytes into the Pan02 tumor tissues, shedding light on their mechanisms of action in cancer immunotherapy.

Inhibiting PARP-1/2 offered an important arsenal for cancer treatments via interfering with DNA repair of cancer cells. Novel PARP-1/2 inhibitors were designed by capitalizing on methyl- or ethyl-substituted piperizine ring to capture the characteristics of adenine-ribose binding site (AD site), and their unique binding features were revealed by the cocrystal structures of compounds 4 and 6 in PARP-1. The investigation on structure-activity relationship resulted in compounds 24 and 32 with high enzymatic potency, binding selectivity, and significantly longer residence time for PARP-1 over PARP-2 (compound 24 , PARP-1: IC 50 = 0.51 nM, PARP-2: IC 50 = 23.11 nM; compound 32 , PARP-1: IC 50 = 1.31 nM, PARP-2: IC 50 = 15.63 nM). Furthermore, compound 24 was determined to be an attractive candidate molecule, which possessed an acceptable pharmacokinetic profile and produced remarkable antitumor activity in both breast cancer xenograft model and glioblastoma orthotopic model in mice, either alone or in combination treatment.

At present, the early diagnosis and treatment of NSCLC has become an international research hotspot. However, how to realize the organic combination of highly sensitive and high-resolution tumor imaging diagnosis and effective treatment, and to provide effective information for the diagnosis and treatment of cancer is still a major problem in the integration of cancer diagnosis and treatment. In this study, based on the Crizotinib has a good targeted inhibitory effect on ALK positive tumor cells, the near-infrared targeted fluorescent dye IR-780 was covalently bound with the drug molecule Crizotinib, thus the near-infrared fluorescent probe IR-780-Crizotinib targeting ALK positive tumor cells was synthesized. The probe structure is confirmed by NMR and MS. The optical properties of the fluorescent probe and the imaging process in ALK positive tumor-bearing mice were analyzed using ultraviolet spectrophotometer, near-infrared fluorescence spectrometer, and near-infrared fluorescence imaging system. The results show that the probe had better photoactivity. In vivo imaging shows that the probe maintained the biological activity of Crizotinib, effectively targeting the tumor site involved with clear imaging, and ultimately excreted from the body. It was confirmed that the probe could be used for the tracking, positioning and targeted therapy of nude mice with ALK positive tumors in vivo, thus exploring a new approach for the clinical application of near-infrared fluorescent probe to detect ALK positive tumors in the future., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Multidrug resistance (MDR), evoked by improper chemotherapeutic practices, poses a serious threat to public health, which leads to increased medical burdens and weakened curative effects. Taking advantage of the enhanced pharmaceutical effect of Schiff base compounds, an aldehyde-modified mesoporous silica SBA-15 (CHO-SBA-15)-bonded anticancer drug combined with doxorubicin hydrochloride (DOX) was synthesized via a Schiff base reaction. Due to the acid-sensitive imine bonds formed between CHO-SBA-15 and DOX, the as-prepared nanocomposites exhibited pH-responsive drug releasing behaviours, resulting in a more enhanced cytotoxic effect on DOX-resistant tumour cells than that of free drugs. Notably, the in vivo studies indicated that mice treated with CHO-SBA-15/DOX composites evidently showed more attenuated systemic toxicity than the free drug molecules. The siliceous mesopore Schiff base-bonded anticancer drug nanocomposite, with minimal chemical modifications, provides a simplified yet efficient therapeutic nanoplatform to deal with drug-resistant cancer., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Background: The metastasis and recurrence of Non-Hodgkin's lymphoma (NHL) is a major cause of morbidity and mortality. Recent work suggests that drugs capable of targeting epigenetic regulatory mechanisms may be well suited to the treatment of such disease progression., Methods: This study was thus designed to evaluate the ability of the novel histone deacetylase (HDAC) inhibitor CUDC-101 to synergize with gemcitabine in order to kill human HUT78 and Pfeiffer NHL cells. To that end, we analyzed the viability of these NHL cells via CCK-8 assay, while the incidence of apoptosis among treated cells was evaluated via Annexin V-FITC/PI staining and by the Western blotting-mediated evaluation of proteins associate with apoptosis and related signaling pathways., Results: We found that CUDC-101 and gemcitabine interacted synergistically to reduce NHL cell viability and to induce the apoptotic death of these cells via the EGFR/ PI3K/Akt and Erk pathways, which were regulated by HDAC signaling pathways., Conclusion: Together, our results highlight the anti-cancer properties of CUDC-101 alone or in combination with gemcitabine as an approach to inducing the apoptotic death of lymphoma cells in vitro, while also offering insight into the underlying molecular mechanisms governing this activity., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Resistance to platinum agents is a crucial challenge in the treatment of cancer using platinum drugs. To overcome the resistance of cells, the survivin protein is supposed to be decreased, since it has previously been found to be overexpressed in drug-resistant cancer cells in anti-apoptosis pathways, while the intracellular effective platinum accumulation should be increased. In the present work, a protamine/hyaluronic acid nanocarrier was used to load survivin siRNA with Pt(IV) loaded outside the coated polyglutamic acid (PGA) by chemical conjugation. The siRNA was released from the co-loaded nanoparticle prior to Pt(IV), in this way, the expression of survivin protein was effectively reduced, which, in turn, could avoid the anti-apoptosis of drug resistant cells. Here, Pt(IV) displayed a sustained release effect and gradually reduced to the toxic Pt(II) species, which reduced drug efflux and enhance apoptosis of the cancer cells. In vitro studies demonstrated that co-loaded nanoparticles resulted in similar cell killing performance in A549/DDP cells (cisplatin resistant) compared with non-siRNA loaded nanoparticles in A549 cells (cisplatin sensitive). NP-siRNA/Pt(IV) exhibited a greatly improved therapeutic effect (TIR, 82.46%) in a nude mice A549/DDP tumor model, with no serious adverse effects observed. Thus, co-loading of Pt(IV) and survivin siRNA nanoparticles could reverse cisplatin resistance and therefore has promising prospects for efficient cancer chemotherapy., (Copyright © 2021 Elsevier B.V. All rights reserved.)

As abnormal PI3K signaling is a feature of many types of cancer, the development of orally active PI3K inhibitors is of great significance for targeted cancer therapy. Through integrating strategies of reducing aromatic character/increasing the fraction of sp 3 carbons together with scaffold hopping, we designed and synthesized two new series of thieno[2,3-d]pyrimidine and thiazolo[5,4-d]pyrimidine derivatives for use as PI3K inhibitors. Our structure-activity relationship studies led to the identification of thieno[2,3-d]pyrimidine 6a and thiazolo[5,4-d]pyrimidine 7a, which exhibited remarkable nanomolar PI3K potency, good antiproliferative activity, favorable pharmacokinetic properties and significant in vivo anti-cancer efficacy. Notably, thiazolo[5,4-d]pyrimidine 7a had better anti-cancer activity than thieno[2,3-d]pyrimidine 6a and is worthy of further pre-clinical evaluation for its use in cancer treatment., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

The tubulin colchicine binding site has been recognized as an attractive drug target to combat cancer, but none of the candidate drugs have been approved for medical treatment. We recently identified a structurally distinct small molecule S-40 as an oral potent tubulin destabilizing agent. Crystal structure analysis of S-40 in a complex with tubulin at a resolution of 2.4 Å indicated that S-40 occupies all 3 zones in the colchicine pocket with interactions different from known microtubule inhibitors, presenting unique effects on assembly and curvature of tubulin dimers. S-40 overcomes paclitaxel resistance and lacks neurotoxicity, which are the main obstacles limiting clinical applications of paclitaxel. Moreover, S-40 harbors the ability to inhibit growth of cancer cell lines as well as patient-derived organoids, induce mitotic arrest and cell apoptosis. Xenograft mouse models of human prostate cancer DU145, non-small cell lung cancer NCI-H1299 and paclitaxel-resistant A549 were strongly restrained without apparent side effects by S-40 oral administration once daily. These findings provide evidence for the development of S-40 as the next generation of orally effective microtubule inhibitors for cancer therapy., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Background: Chemoresistance is emerging as a major barrier to successful treatment in acute myeloid leukemia (AML), and evasion of apoptosis is among the fundamental underlying mechanisms. Therefore, unraveling molecular networks that drive this process constitutes an urgent unmet need. Herein, we aim to characterize the role and molecular mechanism of the tumor necrosis factor ɑ-induced protein 8 (TNFAIP8), a novel anti-apoptotic molecule, in AML chemoresistance., Methods: The expression levels of TNFAIP8 were assessed in AML patients and cell lines by RT-qPCR and western blots. The transcriptional regulation of TNFAIP8 was analyzed with luciferase reporter assay and ChIP followed by RT-qPCR. Functional experiments were conducted to evaluate the effects of TNFAIP8 on apoptosis, drug sensitivity and proliferation of AML cells. Potential effects of TNFAIP8 on the activation of extracellular signal-regulated kinase (ERK) pathway were detected by western blots. CoIP and P21-activated kinase (PAK) pull-down assay were performed to ascertain the upstream target. The overall effects of TNFAIP8 on AML were examined in murine models., Results: Upregulated TNFAIP8 expression was first confirmed in human AML patients and cell lines. E74 like ETS transcription factor 1 (ELF1) was then identified to contribute to its aberrant expression. Through manipulating TNFAIP8 expression, we described its role in protecting AML cells from apoptosis induced by chemotherapeutic agents and in promoting drug resistance. Notably, the leukemia-promoting action of TNFAIP8 was mediated by sustaining activity of the ERK signaling pathway, through an interaction with Rac family small GTPase 1 (Rac1). In addition, in vivo experiments confirmed that TNFAIP8 suppression lowered leukemia infiltration and improved survival., Conclusion: Our data provide a molecular basis for the role of TNFAIP8 in chemoresistance and progression of AML and highlight the unique function of TNFAIP8 as an attractive therapeutic target.

Background: Bruton tyrosine kinase (BTK) inhibitors have demonstrated a high degree of efficacy in the treatment of B cell malignancies characterized by constitutive B cell receptor activation, including chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL)., Methods: The efficacy and safety of zanubrutinib, an investigational highly selective BTK inhibitor, was evaluated in this single-arm, phase 2 study of Chinese patients with relapsed/refractory CLL/SLL. The primary endpoint was overall response rate as assessed by an independent review committee., Results: Of the 91 evaluable patients, 77 (84.6%) achieved a response, with three (3.3%), 54 (59.3%), and 20 (22%) patients achieving a complete response, partial response, and partial response with lymphocytosis, respectively, after a median follow-up of 15.1 months. The estimated 12-month event-free rate for duration of response was 92.9%. The most commonly reported grade ≥ 3 adverse events (AEs) were neutropenia (44%), thrombocytopenia (15.4%), lung infection/pneumonia (13.2%), upper respiratory tract infection (9.9%), and anemia (8.8%). The 12-month overall survival rate was 96%. Eight (9.0%) patients discontinued zanubrutinib due to AEs, and seven (8.0%) patients required at least one dose reduction., Conclusion: Treatment of patients with relapsed/refractory CLL/SLL with zanubrutinib was generally well tolerated and resulted in a high overall response rate, thereby conferring a favorable benefit-risk profile., Trial Registration: Prospectively registered in China public registry (CTR20160890) on December 7, 2016: http://www.chinadrugtrials.org.cn/. Retrospectively registered in ClinicalTrials.gov (NCT03206918) on July 2, 2017.

Patients diagnosed with metastatic breast cancer have a dismal 5-year survival rate of only 24%. The RNA-binding protein Hu antigen R (HuR) is upregulated in breast cancer, and elevated cytoplasmic HuR correlates with high-grade tumors and poor clinical outcome of breast cancer. HuR promotes tumorigenesis by regulating numerous proto-oncogenes, growth factors, and cytokines that support major tumor hallmarks including invasion and metastasis. Here, we report a HuR inhibitor KH-3, which potently suppresses breast cancer cell growth and invasion. Furthermore, KH-3 inhibits breast cancer experimental lung metastasis, improves mouse survival, and reduces orthotopic tumor growth. Mechanistically, we identify FOXQ1 as a direct target of HuR. KH-3 disrupts HuR-FOXQ1 mRNA interaction, leading to inhibition of breast cancer invasion. Our study suggests that inhibiting HuR is a promising therapeutic strategy for lethal metastatic breast cancer.

Flavonoids are a group of polyphenols ubiquitously present in vegetables, fruits and herbal products, despite various known pharmacological activities, few researches have been done about the interaction of flavonoids with breast cancer resistance protein (BCRP). The present study was designed to investigate the inhibitory effects of 99 flavonoids on BCRP in vitro and in vivo and to clarify structure-activity relationships of flavonoids with BCRP. Eleven flavonoids, including amentoflavone, apigenin, biochanin A, chrysin, diosimin, genkwanin, hypericin, kaempferol, kaempferide, licochalcone A and naringenin, exhibited significant inhibition (>50%) on BCRP in BCRP-MDCKII cells, which reduced the BCRP-mediated efflux of doxorubicin and temozolomide, accordingly increased their cytotoxicity. In addition, co-administration of mitoxantrone with the 11 flavonoids increased the AUC 0-t of mitoxantrone in different extents in rats. Among them, chrysin increased the AUC 0-t most significantly, by 81.97%. Molecular docking analysis elucidated the inhibition of flavonoids on BCRP might be associated with Pi-Pi stacked interactions and/or potential Pi-Alkyl interactions, but not conventional hydrogen bonds. The pharmacophore model indicated the aromatic ring B, hydrophobic groups and hydrogen bond acceptors may play critical role in the potency of flavonoids inhibition on BCRP. Thus, our findings would provide helpful information for predicting the potential risks of flavonoid-containing food/herb-drug interactions in humans., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

The phosphoinositide 3-kinase (PI3K) pathway, one of the most commonly activated signaling pathways in human cancers, plays a crucial role in the regulation of cell proliferation, differentiation, and survival. This pathway is usually activated by receptor tyrosine kinases (RTKs), whose constitutive and aberrant activation is via gain-of-function mutations, chromosomal rearrangement, gene amplification and autocrine. Blockage of PI3K pathway by targeted therapy on RTKs with tyrosine kinases inhibitors (TKIs) and monoclonal antibodies (mAbs) has achieved great progress in past decades; however, there still remain big challenges during their clinical application. In this review, we provide an overview about the most frequently encountered alterations in RTKs and focus on current therapeutic agents developed to counteract their aberrant functions, accompanied with discussions of two major challenges to the RTKs-targeted therapy in cancer - resistance and toxicity., (Copyright © 2019. Published by Elsevier Ltd.)

Polypharmacology is a promising paradigm in modern drug discovery. Herein, we have discovered a series of novel PI3K and HDAC dual inhibitors in which the hydroxamic acid moiety as the zinc binding functional group was introduced to a quinazoline-based PI3K pharmacophore through an appropriate linker. Systematic structure-activity relationship studies resulted in lead compounds 23 and 36 that simultaneously inhibited PI3K and HDAC with nanomolar potencies and demonstrated favorable antiproliferative activities. Compounds 23 and 36 efficiently modulated the expression of p-AKT and Ac-H3, arrested the cell cycle, and induced apoptosis in HCT116 cancer cells. Following pharmacokinetic studies, 23 was further evaluated in HCT116 and HGC-27 xenograft models to show significant in vivo anticancer efficacies with tumor growth inhibitions of 45.8% (po, 150 mg/kg) and 62.6% (ip, 30 mg/kg), respectively. Overall, this work shows promise in discovering new anticancer therapeutics by the approach of simultaneously targeting PI3K and HDAC pathways with a single molecule.

Purpose: To evaluate the inhibitory effect of 5-fluorouracil (5-FU) in combination with cisplatin on the proliferation of human osteosarcoma cells in vitro., Methods: Three groups of human osteosarcoma U2OS cells were cultured in DMEM medium supplemented with the following drugs: 20 µg/mL 5-FU, 50 µg/mL 5-FU and 50 µg/mL 5-FU in combination with 0.5 mg/L cisplatin. After culture at 24, 48 and 72 h, the inhibition of proliferation rate of U2OS cells was calculated by CCK-8 cell kit. Cell invasiveness was assessed by Transwell assay. Flow cytometry was used for monitoring the cell apoptosis., Results: 5-FU inhibited the growth of osteosarcoma cells, and the results of different concentrations of 5-FU were significantly different. The growth of U2OS cells decreased significantly within 24-72 h, and the concentration of 5-FU increased with time. The inhibition of the shift was more obvious, and the combined drug inhibition was significantly higher than the 20μg/ml 5-FU Group, 0.5mg/L Cisplatin Group and 50μg/ml 5-FU Group. After 72 h, the mean inhibitory rates of 20 μg/mL 5-FU, 50 μg/mL 5-FU, 50 μg/ml 5-FU in combination with 0.5 mg/L cisplatin, and 0.5 mg/L cisplatin were 12.54±1.26%, 22.17±0.59%, 32.54±1.25%, 20.84±0.83% respectively, and the difference was significant (p<0.05). Results of cell invasion assay showed that after culturing for 48 h, the mean number of cells penetrating the membrane was 22.84±5.27 in the culture group of 0.5 mg/L cisplatin, 30.57±5.68 in the culture group of 20 µg/mL 5-FU, 18.68±4.88 in the culture group of 50 µg/mL 5-FU, and 9.84±3.64 in the culture group of 50 µg/mL 5-FU in combination with 0.5 mg/L cisplatin, respectively, and 72.00±7.52 in the control group, showing statistical differences in each group (p<0.05). The apoptosis of the control group was significantly lower than that of the other groups (p<0.05). Apoptosis rate of the 20μg/mL 5-FU group was significantly lower than that of the 0.5mg/L cisplatin group, the 50μg/mL 5-FU group and the 50 μg/ml 5-FU group in combination with 0.5mg/L cisplatin (p<0.05). There was no difference in apoptosis between 0.5mg/L cisplatin and 50μg/mL 5-FU group (p>0.05)., Conclusion: 5-FU in combination with cisplatin exerts an inhibitory effect on the proliferation and invasion of human osteosarcoma cells in vitro, and can promote cell apoptosis.

Ovarian cancer is a heterogeneous disease with complex molecular and genetic hallmarks. Benefitting from profound understanding of molecular mechanisms in ovarian cancer pathogenesis, novel targeted drugs have been actively explored in preclinical studies and clinical trials. Considered as one of the most potent and effective targeted therapies for the treatment of ovarian cancer, poly (ADP-ribose) polymerase (PARP) inhibitors (PARPis) take advantages of synthetic lethality mechanisms to prevent DNA damage repair in cancer cells and cause their death, especially in cancers with BRCA mutations. Mounting evidence has indicated that the combination of PARPis with cytotoxic drugs or other targeted drugs has shown favorable synergistic effects. Excitingly, the antitumor activity of combination therapy of PARPis has been actively tested in multiple clinical trials and in-vitro or in-vivo experiments. In this review, we will briefly discuss the molecular mechanisms of PARPis combined with other therapeutic small-molecular compounds for the treatment of ovarian cancer.

Glycyrrhetinic acid has been usually studied for their anti-tumor activities. However, the low bioavailability and poor aqueous solubility as well as limited intracellular accumulation have limited their utility. In this present study, a series of new glycyrrhetinic acid conjugates with a triphenylphosphonium cation (TTP + ) moiety, meant to specifically target them to tumor cells mitochondria, have been designed and synthesized. Among them, compound 2f possessed excellent antitumor activities against the tested human cancer cells, and simultaneously exhibited better cell selectivity between cancer cells and normal cells than glycyrrhetinic acid and HCPT. Moreover, 2f significantly induced cell cycle arrest at the G2/M phase, and effectively inhibited cancer cells proliferation and migration. Mechanism studies revealed that 2f triggered apoptosis through the mitochondrial pathway via the collapse of mitochondrial membrane potential, reactive oxygen species production and the activation of caspase-9 and caspase-3., (Copyright © 2019 Elsevier Inc. All rights reserved.)

NSCLC is a worldwide challenge due to its high incidence and poor survival. PI3K-Akt-mTOR (PAM) pathway is one of the major pathways that mediate receptor tyrosine kinases (RTKs) signalling transduction. Aberration in PAM pathway is indicated correlating with poor prognosis of NSCLC. In this article, we highlighted a 2-amino-4-methylquinazoline derivative XH002 as PI3K/mTOR dual inhibitor with outstanding antitumor efficacy. Briefly, XH002 significantly repressed proliferation of PI3KCA mutant and/or P-S6RP, P-RAS40 high expressed NSCLC cells. In vitro, XH002 decreased the phosphorylation of PAM pathway proteins in a dose-dependent and time-dependent way. Further investigation indicated that the cancer cells repression by XH002 derived from inducing cell cycle arrest in G1 phase. Moreover, XH002 remarkably inhibited tumour growth of EGFR-TKIs resistant NCI-H1975 xenograft model by blocking PAM pathway. In conclusion, XH002 is a potent oral PI3K/mTOR dual inhibitor that possesses excellent antitumor efficacy against PIK3CA mutant NSCLC, including which resistant to EGFR-TKIs treatments.

Novel NF-κB inhibitors based on Glycyrrhetinic acid (GA) derivatives containing aminophosphonate ester moieties were rationally designed and synthesized as well as evaluated their antitumor activities using MTT assay. Many target compounds showed potent antitumor activities against the tested human cancer cell lines including cisplatin-resistant cells, and exhibited significant inhibitory activity to the NF-κB with IC 50 values at micromolar concentrations in A549 cells, respectively. Among them, compound 12e possessed excellent antitumor activities against the tested human cancer cell lines and showed low cytotoxicity toward to human normal liver cells. Moreover, 12e caused obvious loss of MMP and significantly induced ROS production, and displayed inhibition of cell migration against A549 cells in vitro. Importantly, 12e arrested the cell cycle at the S phases and ultimately induced cell apoptosis in A549 cells through blockage of NF-κB signaling pathway. Our research provided an efficient strategy for targeting NF-κB antitumor drug development., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Background: c-Myc is overexpressed in different types of cancer, including thyroid cancer, and has been considered undruggable. There is evidence showing that MLN8237, a type of aurora A kinase (AURKA) inhibitor, destabilizes c-Myc proteins in liver cancer cells through disruption of the c-Myc/AURKA complex. However, the role of MLN8237 in thyroid cancer remains largely unclear. The aims of this study were to test the therapeutic potential of MLN8237 in thyroid cancer, and to analyze determinant factors affecting the response of thyroid cancer cells to MLN8237 and clarify the corresponding mechanism. Methods: The phenotypic effects of MLN8237 in thyroid cancer cells were evaluated through a series of in vitro and in vivo experiments, and the mechanism of c-Myc affecting MLN8237 response were explored using Western blot, ubiquitination, and cycloheximide chase assays. Results: The data show that the levels of c-Myc protein were strongly associated with MLN8237 cellular response in thyroid cancer cells. Only the cells with high c-Myc expression exhibited growth inhibition upon MLN8237 treatment. However, MLN8237 barely affected the growth of those with low c-Myc expression. Mechanistically, MLN8237 dramatically promoted proteasomal degradation of c-Myc proteins through disruption of the c-Myc/AURKA complex in the cells with high c-Myc expression. A similar antitumor activity of MLN8237 was also found in xenograft tumor models. Conclusions: The data demonstrate that c-Myc is a major determinant for MLN8237 responsiveness in thyroid cancer cells. Thus, indirectly targeting c-Myc by MLN8237 may be an effective strategy for thyroid cancer overexpressing c-Myc.

A method was developed to synthesize 2,3:7,8-di(alkylenedioxy)-extended analogs of quaternary sanguinarine chloride. 1-Bromo-2-bromomethyl-3,4-alkylenedioxy benzenes and 6,7-alkylenedioxynaphthalen-1-amines were synthesized first. Reactions to construct the target compounds with these two series of synthons involved alterations on a published method for synthesizing 2,3,7,8-tetraoxygenated derivatives of benzo[c]phenanthridinium, substituting benzyl bromides for benzoic aldehydes, prolonging the radical annulation time, and conducting N-methylation with formic acid and NaBH 4 . All the target compounds showed the same or better in vitro growth inhibitory activities against cancer cell lines compared with the positive compound. The structure activity relationship relevant to cytotoxicity and lipophilicity of the target compounds was produced.

A novel PEG-cRGD-conjugated irinotecan derivative BGC0222 was designed and synthesized as antitumor agent. Antitumor activity screening assay indicated that BGC0222 exhibited better in vitro antiproliferation activity than irinotecan and NKTR-102 against HT29, MIA PaCa-2 and MCF-7 tumor cell lines, with IC 50 of 1.83 ± 0.09 μM, 3.95 ± 0.16 μM and 0.68 ± 0.04 μM, respectively, while it displayed better in vivo antiproliferation activity than irinotecan and NKTR-102 in HT-29, MIA PaCa-2, NCI-H446, U-87 MG and MDA-MB-231 xenograft models. The action mechanism of BGC0222 was then investigated by integrin-binding competition (IBC) and chick chorioallantoic membrane (CAM) angiogenesis assays, which indicated that BGC0222 may exert antitumor activity by binding to α v β 3 target and consequently inducing neovascularization effect. Pharmacokinetic analysis showed that BGC0222 could slowly and steadily release irinotecan, which was subsequently metabolized into 7-ethyl-10-hydroxycamptothecin (SN-38) in the whole blood., (Copyright © 2018 Elsevier Masson SAS. All rights reserved.)

Novel quinazoline-2,4(1H,3H)-dione derivatives bearing a 3-amino pyrrolidine moiety were designed and synthesized as PARP-1/2 inhibitors. Structure-activity relationships were examined which revealed a number of potent PARP-1/2 inhibitors with moderate selectivity toward PARP-1 over PARP-2. These compounds had IC50 values against PARP-1 at the 10-9 M level and against PARP-2 at the 10-8 M level. Among all the synthesized compounds, compounds 10 and 11 displayed strong cytotoxicities which are either used as a single agent or in combination with temozolomide (TMZ) in MX-1 cells (10, IC50 < 3.12 μM, PF50 > 10; 11, IC50 = 3.02 μM, PF50 ≈ 10). In vivo tumor growth inhibition was investigated using compound 11 in combination with TMZ, and it was demonstrated that compound 11 could strongly potentiate the cytotoxicity of TMZ in a MX-1 xenograft tumor model. The co-crystal structure of compound 11 complexed with PARP-1 was achieved and demonstrated a unique binding mode.

A series of 18β-glycyrrhetinic acid (GA) conjugated aminobenzothiazole derivatives were designed, synthesized and evaluated for disruption activity of Hsp90-Cdc37 as well as the effects of in vitro cell migration. These compounds exhibited relatively good disruption activity against Hsp90-Cdc37 with IC 50 values in low micromolar range. A docking study of the most active compound 11g revealed key interactions between 11g and Hsp90-Cdc37 complex in which the benzothiazole moiety and the amine chain group were important for improving activity. It is noteworthy that further antitumor activity screening revealed that some compounds exhibited better inhibitory activity than the commercial anticancer drug 5-FU and showed potent suppression activity against drug-resistant cancer cells. In particular, compound 11 g appeared to be the most potent compound against the A549 cell line, at least partly, by inhibition of the activity of Hsp90 and apoptosis induction. The treatment of A549 cells with compound 11g resulted in inhibition of in vitro cell migration through wound healing assay and S phase of cell cycle arrested. In addition, 11g-induced apoptosis was significantly facilitated in A549 cells. Thus, we conclude that GA aminobenzothiazole derivatives may be the potential Hsp90-Cdc37 disruptors with the ability to suppress cells migration and reversed drug-resistant., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

A series of novel imidazo[4,5-d]azepine compounds derived from marine natural product ceratamine A were designed and synthesized in 7 steps. Most compounds exhibited comparable cytotoxicity against five human cancer cell lines (HCT-116, HepG2, BGC-823, A549 and A2780) to natural product ceratamine A. Compound 1k, bearing methoxy group at C-14, C-15 and C-16, showed the best in vitro cytotoxicity, which was better than ceratamine A. The structure and activity relationships study showed that the benzyloxymethyl group on N-3 played an important role on the cytotoxicity., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

A novel bistetrahydrocarboline heptacyclic skeleton and its twenty derivatives were prepared from l-tryptophan through a 15-step stereospecific route. The cytotoxicities of these compounds were tested against six human cancer cell lines including HCT-116, HepG2, BGC-823, MCF-7, A2780, and HT-29. Most of the derivatives with amide side chain exhibited the IC 50 values at the level of 10 -7  M, and a preliminary structure-activity relationship (SAR) was discussed. Both compound 30 with 2-pyridine amide side chain and compound 14 with phthalamide side chain showed the most potent and broad cytotoxicity towards all six cell lines with the IC 50 values at the level of 10 -8  M. Molecular docking of compound 30 indicated it bound to minor groove of DNA duplex., (Copyright © 2017 Elsevier Masson SAS. All rights reserved.)

The aim of this study was to profile somatic mutation spectrum in gallbladder cancers (GBCs), and determine the role of MAP kinase pathway in GBC by a series of in vitro and in vivo studies. We performed targeted massively parallel sequencing of DNA isolated from GBCs and matched blood from 14 GBC patients to search for mutations in 504 genes commonly altered in human cancers. We identified recurrent mutations enriched in several major signaling pathways including MAP kinase, Wnt/β-catenin and NF-κB pathways. Immunohistochemistry analysis further validated overactivation of MAP kinase and Wnt pathways in a panel of GBC samples. By treating GBC cells with MEK inhibitor trametinib, we found that trametinib not only dramatically inhibited the activity of MAPK/ERK pathway, but also blocked the Wnt/β-catenin signaling through decreasing β-catenin expression or suppressing nucleus translocation of β-catenin. Moreover, trametinib inhibited the proliferation of GBC cell in a dose- and time-dependent manner, induced GBC cell apoptosis, and inhibited GBC cell migration and invasion. Growth of xenograft tumors derived from GBC cell line NOZ in nude mice was also significantly inhibited by trametinib. Our data highlight the critical role of MAP kinase pathways in GBC pathogenesis, and may represent therapeutic targets for this cancer.

Cisplatin treatment some times leads to chemoresistance, which is now acknowledged partially due to the inductive expression of progesterone receptor membrane component (PGRMC)1 in ovarian cancer cells. PGRMC1 enhances autophagy, activates cytochrome p450, and inveigles signaling pathways to promote cell survival and reduce the effect of drug treatments. In this study, we give first line evidence that hyperoside inhibits cell viability, triggers autophagy and apoptosis in ovarian cancer cell lines. Mechanistically, PGRMC1-dependent autophagy was utilized by hyperoside to induce apoptotic cell death. Hyperoside induced the conversion of LC3B-I to LC3B-II and the formation of autophagosomes in ovarian cancer cells. Notably, PGRMC1 colocolized with LC3B‑II, and PGRMC1 overexpression enhanced hyperoside-induced autophagy and apoptosis, while PGRMC1 knockdown abrogated the action. Additionally, AKT signaling and Bcl-2 family were also involved in the hyperoside-induced autophagy and apoptosis. Importantly, in cisplatin-resistant ovarian cancer cells where PGRMC1 was overexpressed, hyperoside sensitized the cells to cisplatin treatment. Together these findings indicate hyperoside functions as a complementary therapy for ovarian cancer patients receiving platinum-based therapy.

Glioblastoma is an aggressive tumor that is associated with distinctive infiltrating microglia/macrophages populations. Previous studies demonstrated that chlorogenic acid (5-caffeoylquinic acid, CHA), a phenolic compound with low molecular weight, has an anti-tumor effect in multiple malignant tumors. In the present study, we focused on the macrophage polarization to investigate the molecular mechanisms behind the anti-glioma response of CHA in vitro and in vivo. We found that CHA treatment increased the expression of M1 markers induced by LPS/IFNγ, including iNOS, MHC II (I-A/I-E subregions) and CD11c, and reduced the expression of M2 markers Arg and CD206 induced by IL-4, resulting in promoting the production of apoptotic-like cancer cells and inhibiting the growth of tumor cells by co-culture experiments. The activations of STAT1 and STAT6, which are two crucial signaling events in M1 and M2-polarization, were significantly promoted and suppressed by CHA in macrophages, respectively. Furthermore, In G422 xenograft mice, CHA increased the proportion of CD11c-positive M1 macrophages and decreased the distribution of CD206-positive M2 macrophages in tumor tissue, consistent with the reduction of tumor weight observed in CHA-treated mice. Overall these findings indicated CHA as a potential therapeutic approach to reduce glioma growth through promoting M1-polarized macrophage and inhibiting M2 phenotypic macrophage.

Medulloblastoma (MB) and glioblastoma (GBM) are the most prevalent malignant brain tumors. The identification of novel therapeutic strategies is urgent for MB and GBM patients. Herein, we discovered 13a-(S)-3-Hydroxyl-6,7-dimethoxyphenanthro[9,10-b]-indolizidine (PF403) strongly exhibited inhibitory activity against Hedgehog (Hh) pathway-hyperactivated MB and GBM cells with a 50% inhibitory concentration (IC50) of 0.01 nM. CAT3 was designed and synthesized as the prodrug of PF403 and displayed significant in vivo efficacy against MB and GBM. Mechanistic study revealed that CAT3 inhibited MB and GBM primarily by interrupting the Hh signaling pathway. At the molecular level, PF403 inhibited the cell surface accumulation of the Smoothened (Smo) receptor by directly binding or enhancing the interaction of Smo with the repressor Ptch1. Furthermore, PF403 significantly repressed Gli1 nuclear accumulation and transcription by promoting Sufu-Gli1 and PKA-Gli1 interactions. Collectively, our studies support the hypothesis that CAT3 is a promising therapeutic agent for the treatment of Hh-driven MB and GBM., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Anaplastic lymphoma kinase (ALK) is a highly attractive therapeutic target for the treatment of some non-small cell lung cancer patients. This Letter describes the further SAR exploration on the novel 3-sulfonylpyrazol-4-amino pyrimidine scaffold. This work identified a compound 53 with very good in vitro/in vivo efficacies, good DMPK properties together with better hERG tolerability and it is currently being profiled for the evaluation as a potential pre-clinical candidate., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

The chemical structure of a drug determines its physicochemical properties, further determines its ADME/Tox properties, and ultimately affects its pharmacological activity. Medicinal chemists can regulate the pharmacological activity of drug molecules by modifying their structure. Ring systems and functional groups are important components of a drug. The proportion of non-hydrocarbon atoms among non-hydrogen atoms reflects the heavy atoms proportion of a drug. The three factors have considerable potential for the assessment of the drug-like properties of organic molecules. However, to the best of our knowledge, there have been no studies to systematically analyze the simultaneous effects of the number of aromatic and non-aromatic rings, the number of some special functional groups and the proportion of heavy atoms on the drug-like properties of an organic molecule. To this end, the numbers of aromatic and non-aromatic rings, the numbers of some special functional groups and the heavy atoms proportion of 6891 global approved small drugs have been comprehensively analyzed. We first uncovered three important structure-related criteria closely related to drug-likeness, namely: (1) the best numbers of aromatic and non-aromatic rings are 2 and 1, respectively; (2) the best functional groups of candidate drugs are usually -OH, -COOR and -COOH in turn, but not -CONHOH, -SH, -CHO and -SO3H. In addition, the -F functional group is beneficial to CNS drugs, and -NH2 functional group is beneficial to anti-infective drugs and anti-cancer drugs; (3) the best R value intervals of candidate drugs are in the range of 0.05-0.50 (preferably 0.10-0.35), and R value of the candidate CNS drugs should be as small as possible in this interval. We envision that the three chemical structure-related criteria may be applicable in a prospective manner for the identification of novel candidate drugs and will provide a theoretical foundation for designing new chemical entities with good drug-like properties.

Three series of curcumin derivatives including phosphorylated, etherified, and esterified products of curcumin were synthesized, and their anti-tumor activities were assessed against human breast cancer MCF-7, hepatocellular carcinoma Hep-G2, and human cervical carcinoma HeLa cells. Compared with curcumin, compounds 3, 8, and 9 exhibited stronger antitumor cell line growth activities against HeLa cells. Compound 12 also showed higher antitumor cell line growth activities on MCF-7 cells than curcumin. Among them, 4-((1E,6E)-7-(4-Hydroxy-3-methoxyphenyl)-3,5-dioxohepta-1,6-dienyl)-2-methoxyphenyl dihydrogen phosphate(3) showed the strongest activity with an half maximal inhibitory concentration (IC50) of 6.78 µM against HeLa cells compared with curcumin with an IC50 of 17.67 µM. Stabilities of representatives of the three series were tested in rabbit plasma in vitro, and compounds 3 and 4 slowly released curcumin in plasma. The effect of compound 3 on HeLa cell apoptosis was determined by examining morphological changes by DAPI (4',6-diamidino-2-phenylindole) staining as well as Annexin V-FITC/ Propidium Iodide (PI) double staining and flow cytometry. The results showed that 3 induced cellular apoptosis in a dose-dependent manner. Together our findings show that 3 merits further investigation as a new potential antitumor drug candidate.

Backgrounds: The present study aimed to evaluate benefit of hepatic arterial infusion chemotherapy (HAI) combined with systemic chemotherapy (SCT) for patients with colorectal liver metastases (CLMs) in a palliative setting., Methods: This was a retrospective single-center study including 43 consecutive patients with CLM after failure of standard SCT. Among them, 20 (47 %) patients underwent HAI combined with SCT (Group A) and 23 historical control patients who had received SCT with or without targeted agent treatment (Group B)., Results: The two groups had similar characteristics. Compared with SCT alone, HAI combined with SCT prolonged survival (median 19.8 vs. 9.0 months; P = 0.045). Median hepatic progression-free survival was significantly longer for HAI combined with SCT vs. SCT alone (median 8.1 vs. 4.7 months; P = 0.027), as were response rates (25 and 0 %; P = 0.038) and progression-free survival (median 5.7 vs. 3.0 months; P = 0.02). Three patients (15 %) achieved conversion to potentially curative surgery. Grade 3/4 toxicities for Group A and Group B were neutropenia (5 and 8.7 %, respectively), anemia (5 and 0 %, respectively), and hyperbilirubinemia (0 and 4.3 %, respectively). Other complications were mostly grade 1 or 2., Conclusions: HAI combined with SCT treatment can improve overall survival compared with SCT alone in highly advanced CLM refractory to intravenous chemotherapy.

A new series of 2,4-diamino pyrimidine derivatives with a sulfone-substituted pyrazole right side-chain were discovered as potent anaplastic lymphoma kinase inhibitors. Structure-activity relationship of the left side-chain on phenyl substitutions were explored which delivered many potent ALK inhibitors. Among them, 29a showed favorable pharmacokinetic profiles in rats and dogs together with significant antitumor efficacy in EML4-ALK fusion xenograft model., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

In our study, three series of hydroxamate, 2-aminobenzamide, and trifluoromethyl ketone analogues have been designed and synthesized. The synthesized compounds were investigated for their in vitro antiproliferative activities using the MTT-based assay against three human cancer cell lines including A549, NCI-H661, and U937. Most analogues exhibited higher antiproliferative activities against human acute myeloid leukemia cell U937 than the other two human lung cancer cell lines. Furthermore, the compounds were examined against HDAC1, 2, and 8 isoforms. Docking study of compounds 6h, 9b, and 10a suggested that they might bind tightly to the binding pocket of HDAC2 and/or HDAC8. The results suggest that these compounds might have potential as lead compounds for the development of anti-tumor drugs with HDACs inhibitory activities., (Copyright © 2015 Elsevier Ltd. All rights reserved.)