Design, synthesis and biological evaluation of novel 1H-1,2,4-triazole, benzothiazole and indazole-based derivatives as potent FGFR1 inhibitors viafragment-based virtual screening

Abstract

2020) Design, synthesis and biological evaluation of novel 1H-1,2,4-triazole, benzothiazole and indazole-based derivatives as potent FGFR1 inhibitors viafragment-based virtual screening, Journal of Enzyme Inhibition and Medicinal Chemistry, 35:1, 72-84, ABSTRACTFibroblast growth-factor receptor (FGFR) is a potential target for cancer therapy. We designed three novel series of FGFR1 inhibitors bearing indazole, benzothiazole, and 1H-1,2,4-triazole scaffold via fragmentbased virtual screening. All the newly synthesised compounds were evaluated in vitro for their inhibitory activities against FGFR1. Compound 9d bearing an indazole scaffold was first identified as a hit compound, with excellent kinase inhibitory activity (IC 50 ¼ 15.0 nM) and modest anti-proliferative activity (IC 50 ¼ 785.8 nM). Through two rounds of optimisation, the indazole derivative 9 u stood out as the most potent FGFR1 inhibitors with the best enzyme inhibitory activity (IC 50 ¼ 3.3 nM) and cellular activity (IC 50 ¼ 468.2 nM). Moreover, 9 u also exhibited good kinase selectivity. In addition, molecular docking study was performed to investigate the binding mode between target compounds and FGFR1. GRAPHICAL ABSTRACT ARTICLE HISTORY

The Diverse Roles of TAO Kinases in Health and Diseases

“…The development of inhibitors that disrupt the TAOK2 C-terminal interaction may have potential use in the clinic if the interaction is involved in disease pathology. Recently, various kinase inhibitor candidates have been developed by structure-guided, kinase domain virtual screening [ 85 , 86 ]. This is usually achieved by searching a compound that binds to a target through the quantitative structure–activity relationship model derived from existing molecule datasets [ 85 ].…”

Discovery of 1,6-Naphthyridin-2(1H)-one Derivatives as Novel, Potent, and Selective FGFR4 Inhibitors for the Treatment of Hepatocellular Carcinoma

“…The methyl group substituted at the aniline moiety formed hydrophobic interactions with Leu619 and restricted the rotation of the aniline moiety, thereby enhancing FGFR4-selectivity . Additionally, in our previous study, the heterocycle in the adenine region was not only employed to connect the hydrophobic region I and II but also to adjust the conformation of the hydrophobic region I and II . Thus, in this work, the investigation of different heterocycle scaffolds is the primary goal of the design of selective FGFR4 inhibitors.…”

“…39 Additionally, in our previous study, the heterocycle in the adenine region was not only employed to connect the hydrophobic region I and II but also to adjust the conformation of the hydrophobic region I and II. 40 Thus, in this work, the investigation of different heterocycle scaffolds is the primary goal of the design of selective FGFR4 inhibitors.…”

Current progress, challenges and future prospects of indazoles as protein kinase inhibitors for the treatment of cancer

“…5 ). 53 The structure–activity relationship (SAR) studies of the synthesized derivatives (14a–e) revealed that the substitution of the 3-methoxyphenyl group on the phenyl ring (14a, IC 50 = 15 nM) with larger groups such as 3-ethoxyphenyl (14b, IC 50 = 13.2 nM) and 3-isopropoxyphenyl (14c, IC 50 = 9.8 nM) led to an increase in activity. Interestingly, the presence of an additional fluorine atom on the phenyl ring led to a remarkable improvement in activity (14d, IC 50 = 5.5 nM) compared to its counterpart 14a (IC 50 = 15 nM).…”