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Anaplastic lymphoma kinase (ALK) fusion genes promote a variety of human malignancies. Although several ALK inhibitors have significantly improved disease prognosis in patients with ALK positive cancers, the persistent emergence of acquired drug-resistant mutations remain the major problem in clinic treatment. Adoption of new therapeutic strategies such as proteolysis targeting chimera (PROTAC) to overcome drug resistance in BTK/AR-related cancers have shown promising prospect. Herein, we reported the integrate ALK PROTACs through overall optimization of linker, revealed that subtle structural differences can lead to significant activity difference, indicating the key role of conformation of PROTACs in inducing the formation of E3-PROTAC-target protein ternary complexes. A series of rigid ALK PROTACs were developed through conjugation of Ceritinib and thalidomide, orally bioavailable PROTAC 4B (F = 14.22 %) was obtained by overall optimization of molecular properties. 4B effectively induced long lasting degradation of ALK fusion proteins and strong repression of downstream pathway in Karpas 299 cells (DC 50  = 119.33 nM, Dmax = 97.1 %) and showed comparable anti-proliferative activity to Ceritinib (IC 50  = 3.11 ± 0.08 nM vs IC 50  = 1.31 ± 0.43 nM). Furthermore, 4B significantly inhibited the growth of Karpas 299 xenografts in vivo with TGI of 49.5 % and showed superior anti-proliferative activity against G1202R mutation to Ceritinib (IC 50  = 52.82 nM vs IC 50  = 109.5 nM). Overall, 4B is expected to be a potential treatment for ALK-driven malignancies., 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.)

Glucose transporters play an essential role in cancer cell proliferation and survival and have been pursued as promising cancer drug targets. Using microarrays of a library of new macrocycles known as rapafucins, which were inspired by the natural product rapamycin, we screened for new inhibitors of GLUT1. We identified multiple hits from the rapafucin 3D microarray and confirmed one hit as a bona fide GLUT1 ligand, which we named rapaglutin A (RgA). We demonstrate that RgA is a potent inhibitor of GLUT1 as well as GLUT3 and GLUT4, with an IC 50 value of low nanomolar for GLUT1. RgA was found to inhibit glucose uptake, leading to a decrease in cellular ATP synthesis, activation of AMP-dependent kinase, inhibition of mTOR signaling, and induction of cell-cycle arrest and apoptosis in cancer cells. Moreover, RgA was capable of inhibiting tumor xenografts in vivo without obvious side effects. RgA could thus be a new chemical tool to study GLUT function and a promising lead for developing anticancer drugs., (© 2019 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

α-Mangostin (αM), a traditional natural product with promising application of treating a series of diseases, was limited use in clinical due to its hydrophobicity. Herein, MPEG-PCL nanomicelles were used to embed the αM for resolving hydrophobicity and improving the anti-melanoma effect of the αM. The anti-melanoma activity and potential mechanisms of biodegradable αM/MPEG-PCL nanomicelles were investigated. The αM/MPEG-PCL nanomicelles possessed a stronger effect on anti-melanoma compared to the free αM both in vitro and in vivo with a low cytotoxicity in non-tumor cell lines. In the research of mechanisms, the αM/MPEG-PCL nanomicelles inhibited the proliferation of melanoma cell, induced apoptosis via both apoptosis pathways of intrinsic and exogenous in vitro, as well as suppressed tumor growth and restrained angiogenesis in vivo, which implied that the αM/MPEG-PCL nanomicelles have potential application as a novel chemotherapeutic agent in melanoma therapy.

Melanoma is a highly malignant neoplasm of melanocytes with considerable metastatic potential and drug resistance, explaining the need for new candidates that inhibit tumor growth and metastasis. The signal transducer and activator of the transcription 3 (Stat3) signaling pathway plays an important role in melanoma and has been validated as promising anticancer target for melanoma therapy. In this study, nifuroxazide, an antidiarrheal agent identified as an inhibitor of Stat3, was evaluated for its anti-melanoma activity in vitro and in vivo. It had potent anti-proliferative activity against various melanoma cell lines and could induce G2/M phase arrest and cell apoptosis. Moreover, nifuroxazide markedly impaired melanoma cell migration and invasion by down-regulating phosphorylated-Src, phosphorylated-FAK, and expression of matrix metalloproteinase (MMP) -2, MMP-9 and vimentin. It also significantly inhibited tumor growth without obvious side effects in the A375-bearing mice model by inducing apoptosis and reducing cell proliferation and metastasis. Notably, nifuroxazide significantly inhibited pulmonary metastases, which might be associated with the decrease of myeloid-derived suppressor cells (MDSCs). These findings suggested that nifuroxazide might be a potential agent for inhibiting the growth and metastasis of melanoma.

To promote the application of methoxy poly(ethylene glycol)-cholesterol (mPEG-Chol), mPEG-Chol was used to prepare core-shell micelles encapsulating poorly water-soluble docetaxel (DTX-PM) by modified cosolvent evaporation method. Approaches to enhance DTX entrapment efficiency (EE) and minimize particle size were investigated in detail, including organic and aqueous phase composition, organic/aqueous phase ratio, and polymer concentration. In optimal formulation, micelles had higher EE (97.6%) and drug loading (4.76%) with the diameter of 13.76 ± 0.68 nm and polydispersity index of 0.213 ± 0.006. Transmission electron microscopy (TEM) showed that the micelles were spherical, and differential scanning calorimetry (DSC) analysis proved that DTX was successfully entrapped into mPEG-Chol micelles. The in vitro cytotoxicity experiments displayed that blank micelles had no effect on the growth of SKOV-3, BXPC-3, A549, and HepG-2 cells, demonstrating that mPEG-Chol was one of the biocompatible biomaterials. The half inhibition concentration of DTX-PM on SKOV-3, BXPC-3, A549, and HepG-2 cells were 10.08, 7.6, 28.37, and 125.75 ng/mL, respectively. DTX-PM had the similar antitumor activity to free DTX, indicating that mPEG-Chol was a promising micellar vector for hydrophobic drug delivery. In addition, this work provided a new and facile approach to prepare drug-loaded micelles with controllable performances., (Copyright © 2012 Wiley Periodicals, Inc.)

Small-molecule inhibitors are promising antitumor drugs. We have designed and synthesized a novel multi-targeted inhibitor, 2-methylcarbamoyl-4-{4-[3-(trifluoro-methyl)benzamido]phenoxy}pyridinium (SKLB610), that potently inhibits human tumor growth. In the study, the pharmacokinetic profile of SKLB610 was investigated. A simple, rapid and sensitive high-performance liquid chromatography-ultraviolet detection method was developed for the determination of SKLB610 in rat plasma. Samples were extracted with methanol and SKLB610 was separated on a C18 column using a mobile phase system consisting of 55% acetonitrile and 45% water, with ultraviolet detection at 270 nm. Sorafenib was used as the internal standard. The retention times of SKLB610 and the internal standard were 5.6 and 8.1 min, respectively. The quantification limit was 67 ng/mL. The calibration curves were linear over a concentration range of 0.1-50 µg/mL. The inter-day and intra-day accuracy and precision were within ± 10%. The recovery and stability of the assay were evaluated from spiked rat plasma. The method was successfully applied to a pharmacokinetic study of SKLB610 in rats. The pharmacokinetic profile of SKLB610 indicated that the oral formulations should be further optimized to improve bioavailability and intravenous formulation of SKLB610 should be developed.

Ansamitocin P-3 is a potent anti-tumor maytansinoid found in Actinosynnema pretiosum. However, due to the complexity of the fermentation broth of Actinomycete, how to effectively separate ansamitocin P-3 is still a challenge. In this study, both analytical and preparative high-performance counter-current chromatography were successfully used to separate and purify ansamitocin P-3 from fermentation broth. A total of 28.8 mg ansamitocin P-3 with purity of 98.4% was separated from 160 mg crude sample of fermentation broth in less than 80 min with the two-phase solvent system of hexane-ethyl acetate-methanol-water (0.6:1:0.6:1, v/v/v/v). The purity and structural identification were determined by HPLC, (1)H NMR, (13)C NMR and mass spectroscopy.

(c) Tumor cell proliferation was evaluated through immunohistochemical analysis staining with Ki67 and the statistical data of Ki67 positive cell number were shown on the right. (d) The apoptosis of tumor was determined by cleaved caspase-3 immunohistochemical staining and the statistical data of CC-3 positive cell number were shown on the right. [Extracted from the article]

Glucose transporters play an essential role in cancer cell proliferation and survival and have been pursued as promising cancer drug targets. Using microarrays of a library of new macrocycles known as rapafucins, which were inspired by the natural product rapamycin, we screened for new inhibitors of GLUT1. We identified multiple hits from the rapafucin 3D microarray and confirmed one hit as a bona fide GLUT1 ligand, which we named rapaglutin A (RgA). We demonstrate that RgA is a potent inhibitor of GLUT1 as well as GLUT3 and GLUT4, with an IC50 value of low nanomolar for GLUT1. RgA was found to inhibit glucose uptake, leading to a decrease in cellular ATP synthesis, activation of AMP‐dependent kinase, inhibition of mTOR signaling, and induction of cell‐cycle arrest and apoptosis in cancer cells. Moreover, RgA was capable of inhibiting tumor xenografts in vivo without obvious side effects. RgA could thus be a new chemical tool to study GLUT function and a promising lead for developing anticancer drugs. [ABSTRACT FROM AUTHOR]

Melanoma, the highest degree of malignancy, is one of the most common skin tumors. However, there is no effective strategy to treat melanoma in current clinical practice. Therefore, it is urgent to find an efficient drug to overcome melanoma. Here, the in vitro anticancer effects of a natural product named hinokiflavone on three melanoma carcinoma cell lines (human melanoma A375 and CHL-1 cells, murine melanoma B16-F10 cells) and mechanisms of action were explored. The results of MTT assay revealed that hinokiflavone inhibited cell proliferation of these cell lines in a dose- and time-dependent manner. Interestingly, hinokiflavone showed low toxicity to normal liver cells. Flow cytometry assay and EdU incorporation assay indicated that hinokiflavone affected A375 and B16 cells survival by inducing apoptosis and blocking cell cycle progression at S phase in a concentration-dependent manner. Moreover, hinokiflavone enhanced the reactive oxygen species (ROS) and decreased the mitochondrial membrane potential obviously. Furthermore, hinokiflavone effectively impaired A375 cells migration and invasion, and down-regulated the expression of matrix metalloproteinase (MMP) MMP2 and MMP9. The above-mentioned results demonstrated that hinokiflavone could be a novel chemotherapeutic agent in melanoma treatment by inhibiting cell proliferation, inducing apoptosis and cell cycle arresting and blocking cell migration and invasion. [ABSTRACT FROM AUTHOR]

Polygonati Rhizoma (PR), which contains rich national cultural connotations, is a traditional Chinese medicine with homology of medicine and food. It has been used for a long time as a tonic in China's multi-ethnic medical system, and is also used to treat diseases such as premature graying hair, deficiency of blood and essence, diabetes, hypertension, etc. Meanwhile, PR is often used as food in China, India, South Korea and other Asian countries, which can satisfy hunger and provide many health benefits. This paper systematically reviewed the ethnopharmacology, botany, phytochemistry, pharmacology and related applications research of PR, and provided a reference for the comprehensive applications of PR, including basic research, product development and clinical applications. This paper also refined the national application characteristics of PR, such as rich plant resources, special chemical components and anti-hidden hungry, which laid a foundation for its high value and high connotation development in the future. The literature information was collected systematically from the electronic scientific databases, including PubMed, Science Direct, Google Scholar, Web of Science, Geen Medical, China National Knowledge Infrastructure, as well as other literature sources, such as classic books of herbal medicine. A comprehensive analysis of the above literature confirmed that PR has been used in the ethnic medicine system of Asian countries such as China for thousands of years. In this paper, 12 species including official species that can be used as PR are summarized, which provide rich plant resources for PR. The chemical components in PR are divided into nutritional components and active components. The former not only contains non-starch polysaccharides and fructo-oligosaccharides, which account for about 50% in PR and are recognized as high-quality diet in the world, but also contains inorganic elements and mineral elements. And a total of 199 kinds active ingredients, including saponins, flavonoids, alkaloids, etc., were sorted out by us. The above ingredients make PR have a special property of anti-hidden hunger. Studies have shown that PR has a wide range of pharmacological activities, such as immune regulation, blood glucose regulation, lipid-lowering, antioxidant, anti-tumor, antibacterial, etc. It has been widely used in medicine, food, cosmetics, gardens and other fields. PR, as a classic medicinal material of the same origin, is widely used in the traditional ethnic medicine system. It contains abundant potential plant resources, chemical components and pharmacological activities. This paper also suggests that PR with high application value in food industry, has the potential to become a high-quality coarse grain. Exploring the way of grain and industrialization of PR is beneficial to fully develop the economic value of PR. [Display omitted] • PR is a potential high-quality crop and food that can fight hidden hunger. • The material base and pharmacological mechanism of PR need to be further studied. • Challenges for PR industry are mainly uncontrolled quality and declining wild resources. • Promoting the development of PR for industrialization is conducive to play its value fully. [ABSTRACT FROM AUTHOR]

Antibody-drug conjugates (ADCs), combining monoclonal antibody with high cytotoxicity chemotherapeutic drug (warhead), have been successfully applied for clinical cancer therapy. Linker technology to select and design linker connecting warhead with antibody, is critical to the success of therapeutic ADCs. In this study, three kinds of linkers were designed to connect SN-38, the bioactive metabolite of the anticancer drug irinotecan (CPT-11), which is 100–1000 times more potent than CPT-11, with the anti-HER2 antibody trastuzumab to prepare three different ADC conjugates (T-SN38 A, B and C). Meanwhile, we compared the anti-ovarian cancer effect of these three T-SN38 conjugates with trastuzumab in vitro and in vivo . Our in vitro results showed that T-SN38 A, B and C (drug-to-antibody ratio, DAR = 3.7, 3.2, 3.4) were 2 to 3 times as cytotoxic as SN-38, and the IC 50 for these three conjugates on SKOV-3 cell line at 72 h were 5.2 ± 0.3, 4.4 ± 0.7, and 5.1 ± 0.4 nM respectively. In our in vivo studies, T-SN38 conjugates had well targeting ability for tumor tissue and all three of them had much higher anti-ovarian cancer potency than trastuzumab. Among of them, T-SN38 B, which coupled SN-38 with trastuzumab by a carbonate bond, has the best anti-ovarian cancer potency. In conclusion, the novel HER2-targeting ADCs T-SN38 have great potential for HER2-positive ovarian cancer. Moreover, the SN-38-Linkers designed in this study can also be used to connect with other antibodies for the therapy of other cancers. [ABSTRACT FROM AUTHOR]

A series of novel nitrogen mustard-based fluorescent compounds were reported with good mitochondrial targeting ability and DNA alkylation activity. The results indicated that these compounds can be used directly as reporting and imaging agents for gel electrophoresis and flow cytometry without the necessity of additional fluorescent tagging agents. Notably, the compound CXL92 displayed highly selective activity against lung cancer cell line A549 with an IC 50 value of 0.32 μM compared to normal cell (LO2). Nitrogen mustard-based fluorescent DNA alkylation dyes with highly selective activity against lung cancer cell compared to normal cell. Image 1 • Mitochondria-targeted DNA alkylation dyes. • Novel fluorescence-visible DNA cross-linking agents. • Highly active and selective anticancer agent with mitochondrial-targeted ability. [ABSTRACT FROM AUTHOR]