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Background: Histone deacetylase inhibitors (HDACIs) are important as anticancer agents. Objective: This study aimed to investigate some key structural features of HDACIs via the design, synthesis and biological evaluation of novel benzamide-based derivatives. Methods: Novel structures, designed using a molecular modification approach, were synthesized and biologically evaluated. Results: The results indicated that a subset of molecules with CH 3 /NH 2 at R 2 position possess selective antiproliferative activity. However, only those with an NH 2 group showed HDACI activity. Importantly, the shorter the molecule length, the stronger HDACI. Among all, 7j was the most potent HDAC1-3 inhibitor and antiproliferative compound. Conclusion: The results of the present investigation could provide valuable structural knowledge applicable for the development of the HDACIs and benzamide-based antiproliferative agents in the future.

Lead optimization as a bottleneck in the process of drug discovery is conducted to tackle problems associated with poor pharmacokinetics, continuous emergence of drugresistance, adverse side effects and drug-drug interactions of known pharmaceuticals. Due to the intensive application of multi-targeted tyrosine kinase inhibitors (MTKI) in various pathological conditions, optimization of their structures has always been the focus of intensive medicinal chemistry research efforts. The current review portrays the application of scaffold hopping, bioisosterism, structure-based, and hybrid-based drug design methods in the optimization of lead compounds aiming to enhance their usefulness as novel drugs. Then, the review proceeds with examples of structural modifications carried out, particularly on multi-targeted drugs already available on the market. The demonstrated examples cover structural modifications on 7 well-known drugs during the last twenty years. The application of the above-mentioned strategies has led to the generation of 52 new multitargeted tyrosine kinase inhibitors. Most of the optimized compounds showed improved properties compared to their parent lead compound. The rationales behind the applied modifications and the achieved outcomes were discussed to present practical examples to the researchers engaged in the area., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Histone deacetylases (HDACs) are overexpressed in cancer, and their inhibition shows promising results in cancer therapy. In particular, selective class I HDAC inhibitors such as entinostat are proposed to be more beneficial in breast cancer treatment. Computational drug design is an inevitable part of today's drug discovery projects because of its unequivocal role in saving time and cost. Using three HDAC inhibitors trichostatin, vorinostat, and entinostat as template structures and a diverse fragment library, all synthetically accessible compounds thereof (∼3200) were generated virtually and filtered based on similarity against the templates and PAINS removal. The 298 selected structures were docked into the active site of HDAC I and ranked using a calculated binding affinity. Top-ranking structures were inspected manually, and, considering the ease of synthesis and drug-likeness, two new structures (3a and 3b) were proposed for synthesis and biological evaluation. The synthesized compounds were purified to a degree of more than 95% and structurally verified using various methods. The designed compounds 3a and 3b showed 65-80 and 5% inhibition on HDAC 1, 2, and 3 isoforms at a concentration of 10 μM, respectively. The novel compound 3a may be used as a lead structure for designing new HDAC inhibitors.

A new series of 1,3,5-trisubstituted 2-pyrazolines for the inhibition of cyclooxygenase-2 (COX-2) were synthesized. The designed structures include a COX-2 pharmacophore SO 2 CH 3 at the para-position of the phenyl ring located at C-5 of a pyrazoline scaffold. The synthesized compounds were tested for in vitro COX-1/COX-2 inhibition and cell toxicity against human colorectal adenocarcinoma cell lines HT-29. The lead compound (4-chlorophenyl){5-[4-(methanesulfonyl)phenyl]-3-phenyl-4,5-dihydro-1H-pyrazol-1-yl}methanone (16) showed significant COX-2 inhibition (IC 50 =0.05±0.01 μM), and antiproliferative activity (IC 50 =5.46±4.71 μM). Molecular docking studies showed that new pyrazoline-based compounds interact via multiple hydrophobic and hydrogen-bond interactions with key binding site residues of the COX-2 enzyme., (© 2021 Wiley-VHCA AG, Zurich, Switzerland.)

Objective: A new family of 3'-(Mono, di or tri-substituted phenyl)-4'-(4-(methylsulfonyl) phenyl) spiroisoxazoline derivatives containing indanone spirobridge was designed, synthesized, and evaluated for their selective COX-2 inhibitory potency and cytotoxicity on different cell lines., Methods: A synthetic reaction based on 1,3-dipolar cycloaddition mechanism was applied for the regiospecific formation of various spiroisoxazolines. The activity of the newly synthesized compounds was determined using in vitro cyclooxygenase inhibition assay. The toxicity of the compounds was evaluated by MTT assay. In addition, induction of apoptosis, and expression levels of Bax, Bcl-2 and caspase-3 mRNA in MCF-7 cells were evaluated following exposure to compound 9f. The docking calculations and molecular dynamics simulation were performed to study the most probable modes of interactions of compound 9f upon binding to COX-2 enzyme., Results: The docking results showed that the synthesized compounds were able to form hydrogen bonds with COX-2 involving methyl sulfonyl, spiroisoxazoline, meta-methoxy and fluoro functional groups. Spiroisoxazoline derivatives containing methoxy group at the C-3' phenyl ring meta position (9f and 9g) showed superior selectivity with higher potency of inhibiting COX-2 enzyme. Furthermore, compound 9f, which possesses 3,4-dimethoxyphenyl on C-3' carbon atom of isoxazoline ring, exhibited the highest COX-2 inhibitory activity, and also displayed the most potent cytotoxicity on MCF-7 cells with an IC 50 value of 0.03 ± 0.01 µM, comparable with that of doxorubicin (IC 50 of 0.062 ± 0.012 µM). The results indicated that compound 9f could promote apoptosis. Also, compared to the control group, the mRNA expression of Bax and caspase-3 significantly increased, while that of Bcl-2 significantly decreased upon exposure to compound 9f which may propose the activation of mitochondrial-associated pathway as the mechanism of observed apoptosis., Conclusion: In vitro biological evaluations accompanied with in silico studies revealed that indanone tricyclic spiroisoxazoline derivatives are good candidates for the development of new anti-inflammatory and anticancer (colorectal and breast) agents., (Copyright © 2020. Published by Elsevier Ltd.)

To develop inhibitors blocking VEGFR2 and the Raf/MEK/ERK mitogen-activated protein kinase signaling pathway new compounds based on sorafenib were designed, synthesized and biologically evaluated. Using de novo design method, a library of new ligands was generated and expanded. Considering in silico binding affinity towards VEGFR2, synthetic feasibility, and drug-likeness property, some of the designed ligands were selected for synthesis and screening for their in vitro antiproliferative activities against two cancer cell lines (HT-29 and A549). Four compounds (13a, 14a, 14l and 15b) exhibited stronger antiproliferative activity (with IC 50 values of 13.27, 6.62, 12.74, 3.38 μM, respectively) against HT-29 cells compared to that of the positive reference drug sorafenib (IC 50  = 17.28 μM). Notably, compound 15b demonstrated the highest activity, and in particular, it induced HT-29 apoptosis, increased intracellular reactive oxygen species level, arrested cell cycle at G0/G1 phase, and influenced the expression of apoptosis- and cell cycle-related proteins. 15b compound can effectively block the Raf/MEK/ERK pathway and inhibit VEGFR2 phosphorylation. Molecular docking revealed that 15b can bind well to the active site of VEGFR2 receptor. Collectively, 15b may be considered as a promising compound amenable for further investigation for the development of new anticancer agents., 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 © 2020 Elsevier Masson SAS. All rights reserved.)

Cisplatin is a broadly prescribed anti-tumor agent for the treatment of diverse cancers. Therapy with cisplatin, however, is associated with various adverse effects including nephrotoxicity and ototoxicity. AMP kinase (AMPK), an evolutionarily conserved enzyme, functions as the fundamental regulator of energy homeostasis. While AMPK activation protects normal tissues against cisplatin-induced toxicities, its impact in cancer is context-dependent and there is no single, uniform role for AMPK. On one hand, some report that AMPK activation augments cisplatin-induced apoptosis in cancer, while on the other hand, few reports indicate that AMPK activation rescues cancer cells from the cytotoxicity induced by cisplatin. Here we review the most salient signaling pathways regulated by AMPK with an emphasis on their relation to cisplatin toxicity and yet discuss context-dependent functions of AMPK in cancer., (Copyright © 2019 Elsevier Inc. All rights reserved.)

A tumor is defined as a group of cancer cells and 'surrounding' stromal bio-entities. Alongside the extracellular matrix (ECM) in the tumor microenvironment (TME), the stromal cells play key roles in cancer affliction and progression. Carcinoma-associated fibroblasts (CAFs) in the area of the tumor, whether activated or not, dictate the future of tumor cells. The CAFs and corresponding secreted growth factors (GFs), which mediate the crosstalk within the TME, can be targeted in therapies directed at the stroma. The impact of the fibroblast growth factor-fibroblast growth factor receptor (FGF-FGFR) signaling pathway in different kinds of tumors has been explored. Several tyrosine kinase inhibitors (TKIs), monoclonal antibodies (mAbs), and ligand traps targeting the formation of FGF-FGFR complex are in preclinical or early development phases. Moreover, there are numerous studies in the literature reporting the application of phage display technology for the development of peptides and proteins capable of functioning as FGF mimetics or traps, which are able to modulate FGF-related signaling pathways. In this review, prominent research in relation to phage display-assisted ligand identification for the FGF/FGFR system is discussed., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Background: There is an urgent need to improve efficacy of chemotherapeutics to overcome resistance in cancer treatment. Sphingosine kinase-2 (SphK2) a key regulator of sphingolipid signaling has been rationalized as an important therapeutic target. We evaluated the role of SphK2 in doxorubicin (DOX)-induced apoptosis of NSCLC cells via altering c-FLIPS, MCL-1 and survivin expressions in order to overcome chemoresistance., Methods: Proliferation and apoptosis were evaluated by MTT assay and DAPI staining, respectively. Cell population in each phase of cell cycle was determined by flow cytometric assay. Gene and protein expression levels were examined by quantitative RT-PCR and western blot analysis, respectively., Results: Phorbol myristate acetate (PMA), a SphK2 stimulator, decreased cell death induced by IC 50 of DOX (1.1 µM) to around 70% (p<0.01). Cell cycle analysis revealed a significant accumulation of the cells in S phase with a marked decrease in sub G1 phase when we incubated the cells with combined treatment of PMA and DOX (p<0.05). Adding ABC294640 (40 µM), a SphK2 inhibitor, significantly abolished PMA effect on cell survival (p<0.01). Survivin expression was significantly diminished by applying ABC294640 either alone or in DOX treated cells followed by increase in cell death (p<0.05), however, there was no significant change in MCL-1 expression by ABC294640 either alone or in DOX treated cells (p=0.16) and (p=0.06), respectively., Conclusion: Identifying cancer patients with high SphK2 expression and then inhibiting of SphK2 activity can be considered as an important strategy to increase the efficacy of DOX in the induction of apoptosis., Competing Interests: Conflict of Interest: Authors declare no conflicts of interest., (© Georg Thieme Verlag KG Stuttgart · New York.)

CD24 (cluster of differentiation 24) is a small heavy glycosylated protein, which is overexpressed in many cancer and some cancer stem cells and is associated with the development, invasion, and metastasis of cancer cells. The exact role of CD24 in these processes is not fully understood, however, in this article, it has been tried to present a collection of cancer-related mechanisms attributed to CD24. Based on the literature, CD24 dis-regulates different signaling pathways in various cancer cells, including; Src kinases, STAT3, EGFR, Wnt/β-catenin and MAPK. Src kinases play an important role in the signaling pathways which activate p38 MAPK and STAT3 pathways. Akt and ERK are downstream effectors of CD24-activated EGFR, which promote cell proliferation, invasion and metastasis. CD24 increases the expression of HER2 by the activation of NF-κB transcription factor. Moreover, CD24 up-regulates the expression of miR-21 oncomir through the activation of Src kinases. Identification of the details of these pathways and also new pathways will help researchers to explore new CD24 targeted therapies., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.)

Todays, after four decades from the discovery of monoclonal antibodies by Kohler and Milstein in 1975, a dozen of antibodies are used in cancer targeted therapy with different strategies. The success of these antibodies depends on the specificity of antigens expressed on the cancer cells. Epithelial Cell Adhesion Molecule (EpCAM), a homophilic cell-cell adhesion glycoprotein is a well- known tumor antigen, which expresses on epithelial tumors and circulating tumor cells as well as cancer stem cells. The EpCAM signaling pathway is associated with proliferation, differentiation and adhesion of epithelial cancer cells. Here we review EpCAM structure, expression profile and its signaling pathway in cancer cells. In addition, we focused on structure, mechanism of action and success of anti EpCAM antibodies which have been used in different clinical trials. Based on literatures, Edrecolomab showed limited efficacy in the phase III studies. The wholly human monoclonal antibody Adecatumumab is dose- and target-dependent in metastatic breast cancer patients expressing EpCAM. The chimeric antibody, Catumaxomab, has been approved for the treatment of malignant ascites; however, this Mab showed considerable results in intrapleural administration in cancer patients. Anti EpCAM toxin conjugated antibodies like, Oportuzumab Monatox (scFv antibody and Pseudomonas exotoxin A (ETA)), Citatuzumab Bogatox (Fab fragment with bouganin toxin) and immono-conjugate antibody Tucotuzumab (monoclonal antibody with IL2), have shown acceptable results in different clinical trials. Almost, all of the antibodies were well-tolerated; however, still more clinical trials are needed for the approval of antibodies for the treatment of specific tumors., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.)

Purpose: Cancer is one of the most important life-threatening diseases in the world. The current efforts to combat cancer are being focused on molecular-targeted therapies. The main purpose of such approaches is based on targeting cancer cell-specific molecules to minimize toxicity for the normal cells. RON (Recepteur d'Origine Nantais) tyrosine kinase receptor is one of the promising targets in cancer-targeted therapy and drug delivery., Methods: In this review, we will summarize the available agents against extracellular domain of RON with potential antitumor activities., Results: The presented antibodies and antibody drug conjugates against RON in this review showed wide spectrum of in vitro and in vivo antitumor activities promising the hope for them entering the clinical trials., Conclusion: Due to critical role of extracellular domain of RON in receptor activation, the development of therapeutic agents against this region could lead to fruitful outcome in cancer therapy.