Development of new TAK-285 derivatives as potent EGFR/HER2 inhibitors possessing antiproliferative effects against 22RV1 and PC3 prostate carcinoma cell lines.

Epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor 2 (HER2) protein tyrosine kinases co-expressed in various cancers such as ovarian, breast, colon, and prostate subtypes. Herein, new TAK-285 derivatives (9a-h) were synthesised, characterised, and biologically evaluated as dual EGFR/HER2 inhibitors. Compound 9f exhibited IC50 values of 2.3 nM over EGFR and 234 nM over HER2, which is 38-fold of staurosporine and 10-fold of TAK-285 over EGFR. Compound 9f also showed high selectivity profile when tested over a small kinase panel. Compounds 9a-h showed IC50 values in the range of 1.0-7.3 nM and 0.8-2.8 nM against PC3 and 22RV1 prostate carcinoma cell lines, respectively. Cell cycle analysis, apoptotic induction, molecular docking, dynamics, and MM-GBSA studies confirmed the plausible mechanism(s) of compound 9f as a potent EGFR/HER2 dual inhibitor with an effective antiproliferative action against prostate carcinoma.

Design, Synthesis, Biological Evaluation, and Molecular Dynamics Studies of Novel Lapatinib Derivatives.

Co-expression of the epidermal growth factor receptor (EGFR, also known as ErbB1) and human epidermal growth factor receptor 2 (HER2) has been identified as a diagnostic or prognostic sign in various tumors. Despite the fact that lapatinib (EGFR/HER2 dual inhibitor) has shown to be successful, many patients do not respond to it or develop resistance for a variety of reasons that are still unclear. As a result, new approaches and inhibitory small molecules are still needed for EGFR/HER2 inhibition. Herein, novel lapatinib derivatives possessing 4-anilinoquinazoline and imidazole scaffolds (6a-l) were developed and screened as EGFR/HER2 dual inhibitors. In vitro and in silico investigations revealed that compound 6j has a high affinity for the ATP-binding regions of EGFR and HER2. All of the designed candidates were predicted to not penetrate the BBB, raising the expectation for the absence of CNS side effects. At 10 µM, derivatives possessing 3-chloro-4-(pyridin-2-ylmethoxy)aniline moiety (6i-l) demonstrated outstanding ranges of percentage inhibition against EGFR (97.65-99.03%) and HER2 (87.16-96.73%). Compound 6j showed nanomolar IC50 values over both kinases (1.8 nM over EGFR and 87.8 nM over HER2). Over EGFR, compound 6j was found to be 50-fold more potent than staurosporine and 6-fold more potent than lapatinib. A kinase selectivity panel of compound 6j showed poor to weak inhibitory activity over CDK2/cyclin A, c-MET, FGFR1, KDR/VEGFR2, and P38a/MAPK14, respectively. Structure-activity relationship (SAR) that were obtained with different substitutions were justified. Additionally, molecular docking and molecular dynamics studies revealed insights into the binding mode of the target compounds. Thus, compound 6j was identified as a highly effective and dual EGFR/HER2 inhibitor worthy of further investigation.

Chemical genetics-based discovery of indole derivatives as HCV NS5B polymerase inhibitors.

In order to identify the inhibitors of hepatitis C virus (HCV) replication with a novel scaffold via a mechanistically unbiased approach, we screened our in-house library composed of ∼6000 compounds with various chemical structures by using the renilla luciferase-linked genotype 2a reporter virus, and we identified a series of compounds containing an indole moiety that were active against HCV replication. Based on this result, we further synthesized three groups of indole derivatives and evaluated their inhibitory effects on HCV replication. In the present structure-activity relationship study of these indole derivatives, we discovered that compound 12e was the most potent inhibitor of HCV replication with minimal cytotoxicity (EC50 = 1.1 µM, EC90 = 2.1 µM, and CC50 = 61.8 µM). We also confirmed that compound 12e caused a dose- and time-dependent reduction of viral RNA as well as viral protein levels in both genotype 2a J6/JFH1 RNA-transfected cells and genotype 1b Bart79I subgenomic replicon cells. Finally, a genetic mapping study of mutant viruses resistant to compound 12e revealed that NS5B RNA polymerase was the potential target. This finding was further validated by demonstration of inhibition of NS5B RNA polymerase in vitro by compound 12e (IC50 = 292 nM). Compound 12e may serve as a valuable candidate for the development of a new class of HCV NS5B RNA polymerase inhibitors in the future.