Search

Despite the success of imatinib in CML therapy through Bcr-Abl inhibition, acquired drug resistance occurs over time in patients. In particular, the resistance caused by T315I mutation remains a challenge in clinic. Herein, we embarked on a structural optimization campaign aiming at discovery of novel Bcr-Abl inhibitors toward T315I mutant based on previously reported dibenzoylpiperazin derivatives. We proposed that incorporation of flexible linker could achieve potent inhibition of Bcr-Abl T315I by avoiding steric clash with bulky sidechain of Ile315. A library of 28 compounds with amino acids as linker has been developed and evaluated. Among them, compound AA2 displayed the most potent activity against Bcr-Abl WT and Bcr-Abl T315I , as well as toward Bcr-Abl driven K562 and K562R cells. Further investigations indicated that AA2 could induce apoptosis of K562 cells and down regulate phosphorylation of Bcr-Abl. In summary, the compounds with amino acid as novel flexible linker exhibited certain antitumor activities, providing valuable hints for the discovery of novel Bcr-Abl inhibitors to overcome T315I mutant resistance, and AA2 could be considered as a candidate for further optimization., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Our recent investigation is focused on the discovery of anti-angiogenesis agents. Vascular normalization induced by anti-angiogenic agent appears to be a promising strategy. We have developed novel angiogenesis inhibitors with potency of promoting vascular normalization. Herein, we reported the design, synthesis and preliminary evaluation of proteolysis-targeting chimera (PROTACs) based on the previously developed anti-angiogenesis agents. Two PROTACs exhibited potent VEGFR-2 inhibition and anti-proliferative activity against HUVECs. Moreover, they were capable of reducing protein levels of VEGFR-2 in EA.hy926 cells without significant cytotoxicity against HEK293 cells. The novel PROTACs could be used to normalize the abnormal vessels, resulting in efficient delivery of drugs., 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.)

Angiogenesis is modulated by a multitude of pro-angiogenic factors including VEGFR-2, Tie-2, and EphB4. Moreover, their crosstalk also had been well elaborated. We have identified several diarylurea-based VEGFR-2 inhibitors as potential anti-angiogenesis agents. As a continuation to our previous research, two series of diaryl malonamide and diaryl thiourea derivatives have been developed as multiplex VEGFR-2/Tie-2/EphB4 inhibitors. Interestingly, the biological evaluation indicated that several compounds bearing trifluoromethyl or trifluoromethoxyl exhibited promising multiplex inhibition against angiogenesis-related VEGFR-2, Tie-2, and EphB4. The representative compound (18a) displayed both potent multi-targeted RTK inhibition and considerable antiproliferative activities against human umbilical vein endothelial cells (EA.hy926). These results will contribute to the discovery of novel muti-targeted anti-angiogenesis agents., (Copyright © 2017 Elsevier Masson SAS. All rights reserved.)

Abstract Aberrant angiogenesis is a hallmark of various diseases including cancers. VEGFR-2 inhibitors have been utilized as anti-angiogenic agents for several years. However, compensatory activation of various receptor tyrosine kinases (RTK) could induce the occurrence of resistance. We previously reported a series of multi-target inhibitors of VEGFR-2, Tie-2, and EphB4 as anti-angiogenic agents. These inhibitors might be a promising strategy to overcome the resistance induced by compensatory activation. In order to expand the structural diversity of these multiple RTK inhibitors, we described herein the design, synthesis, and evaluation of a novel class of triplet VEGFR-2/TIE-2/EphB4 inhibitors. The biological evaluation indicated that five compounds (6b, 6d, 6e, 7e , and 7g) exhibited simultaneous VEGFR-2/Tie-2/EphB4 inhibitory activities with IC 50 values less than 50 nM. Graphical abstract Image 1 As a continuation to our previous research, a series of novel anti-angiogenic agents with simultaneous RTK inhibition profile were developed. Highlights • Multi-target inhibitors based on the compensatory of angiogenic RTKs. • Several compounds exhibited simultaneously inhibitory potency. • 1,2,3-Triazole is a novel scaffold of triple RTK inhibitors. [ABSTRACT FROM AUTHOR]

VEGFR-2, TIE-2, and EphB4 are essential for both angiogenesis and tumorigenesis. Herein, we designed and prepared three classes of multi-target inhibitors based on the extensive sequence homology along the kinase domain of angiogenic RTKs. Biological evaluation indicated that these multi-target inhibitors exhibited considerable potential as novel anti-angiogeneic and anticancer agents. Among them, a diaryl thiourea bearing 1 H -indazole-3-amine (16a) displayed the most potent RTK inhibition and excellent selectivity. It also showed inhibition on viability of human umbilical vein endothelial cells and anti-proliferation against a broad spectrum of cancer cells. Therefore, 1 H -indazole-3-amine could serve as a promising hinge binding group for multi-target inhibitors of VEGFR-2, Tie-2, and EphB4. [ABSTRACT FROM AUTHOR]

A series of 2-phenoxy-N-phenylacetamides were designed and synthesized with a view to develop novel anticancer agents. All compounds were prepared with varied substitutions in the phenyl ring of aniline and evaluated for their anticancer activity. The majority of them displayed a moderate degree of cytotoxicity against several human cancer cell lines. Six compounds displayed potent cell growth inhibitory activity with IC values below 20 μM. Two compounds ( TC-5 and TC-14) exhibited the most pronounced antiproliferative activity equivalent to or higher than that of positive control. The structure - activity relationship of these anticancer agents has been reviewed. The results indicate that incorporation of halogen into the benzene ring is beneficial for anticancer activity. [ABSTRACT FROM AUTHOR]

Recently approved multi-target inhibitors of receptor tyrosine kinases (RTKs) have significantly improved the clinical treatment of cancers. A series of N , N ′-diarylureas incorporated with aromatic heterocycle have been designed, synthesized and evaluated as novel multi-target RTK inhibitors. The preliminary biological evaluation indicated that several compounds exhibited comparable potency with Sorafenib. Among them, compound 6f was identified as the most potent multikinase inhibitor of EGFR, KDR and FGFR1 with IC 50 values of 14.83 nM, 21.57 nM, and 28.23 nM, respectively. These compounds expanded the structural diversity of diarylureas as RTK inhibitors. The results demonstrated that compound 6f could be served as novel lead compound for further development of multi-target RTK inhibitors. [ABSTRACT FROM AUTHOR]

A series of N,N' -dibenzoylpiperazine derivatives incorporated with 1 H -indazol-3-amine have been designed, synthesized and evaluated as novel Bcr-Abl inhibitors. Several title compounds exhibited potent inhibitory activity against Bcr-Abl wild type as well as T315I mutant. Two compounds, 11a and 12c , strongly suppressed the activity of native and mutant Bcr-Abl. In particular, 11a exhibited comparable potency with that of Imatinib. It potently inhibited both Bcr-Abl WT and Bcr-Abl T315I with IC 50 values of 0.014 μM and 0.45 μM, respectively. Furthermore, compound 11a also inhibited the proliferation of K562 leukemia cancer cells. Therefore, it could serve as promising lead compound for further optimization of Bcr-Abl WT and Bcr-Abl T315I inhibitors. [ABSTRACT FROM AUTHOR]