Search

FMS-like tyrosine kinase 3 (FLT3) enzyme overexpression and mutations are the most common molecular abnormalities associated with acute myeloid leukemia (AML). In addition, recent studies investigated the role of tropomyosin receptor kinase A (TrKA) enzyme fusions in promoting AML growth and survival. Based on these premises, targeting both kinases using dual inhibitors would constitute a promising therapeutic approach to target resistant AML. Guided by ligand-based design and structure simplification of the FLT3 inhibitor, quizartinib, we developed a benzimidazole-based small molecule, 4ACP, that exhibited nanomolar activity against wild-type FLT3, FLT3-Internal tandem duplications (FLT3-ITD), and FLT3-D835Y (FLT3-TKD) mutation (IC 50  = 43.8, 97.2, and 92.5 nM respectively). Additionally, 4ACP demonstrated potent activity against colon cancer KM12 cell line (IC 50  = 358 nM) and subsequent mechanistic deconvolution identified TrKA enzyme as a second plausible target (IC 50  = 23.6 nM) for our compound. 4ACP manifested preferential antiproliferative activity against FLT3-ITD positive AML cell lines (MV4-11 IC 50  = 38.8 ± 10.7 nM and MOLM-13 IC 50  = 54.9 ± 4.1 nM), while lacking activity against FLT3-ITD negative AML cell lines. Western blot analysis confirmed 4ACP ability to downregulate ERK1/2 and mTOR signaling downstream of FLT3-ITD in AML cells. Furthermore, 4ACP prompted apoptotic and necrotic cell death and G0/G1 cell cycle arrest as indicated by cell cycle analysis. 4ACP did not show cytotoxic effects on normal BNL and H9c2 cells and demonstrated decreased activity against c-Kit enzyme, hence, indicating lower probability of synthetic lethal toxicity and a relatively safer profile. In light of these data, 4ACP represents a novel FLT3/TrKA dual kinase inhibitor for targeted therapy of AML., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Aurora B is a pivotal cell cycle regulator where errors in its function results in polyploidy, genetic instability, and tumorigenesis. It is overexpressed in many cancers, consequently, targeting Aurora B with small molecule inhibitors constitutes a promising approach for anticancer therapy. Guided by structure-based design and molecular hybridization approach we developed a series of fifteen indolin-2-one derivatives based on a previously reported indolin-2-one-based multikinase inhibitor (1). Seven derivatives, 5g, 6a, 6c-e, 7, and 8a showed preferential antiproliferative activity in NCI-60 cell line screening and out of these, carbamate 6e and cyclopropylurea 8a derivatives showed optimum activity against Aurora B (IC 50  = 16.2 and 10.5 nM respectively) and MDA-MB-468 cells (IC 50  = 32.6 ± 9.9 and 29.1 ± 7.3 nM respectively). Furthermore, 6e and 8a impaired the clonogenic potential of MDA-MB-468 cells. Mechanistic investigations indicated that 6e and 8a induced G2/M cell cycle arrest, apoptosis, and necrosis of MDA-MB-468 cells and western blot analysis of 8a effect on MDA-MB-468 cells revealed 8a's ability to reduce Aurora B and its downstream target, Histone H3 phosphorylation. 6e and 8a displayed better safety profiles than multikinase inhibitors such as sunitinib, showing no cytotoxic effects on normal rat cardiomyoblasts and murine hepatocytes. Finally, 8a demonstrated a more selective profile than 1 when screened against ten related kinases. Based on these findings, 8a represents a promising candidate for further development to target breast cancer via Aurora B selective inhibition., (Copyright © 2021 Elsevier Inc. All rights reserved.)

In light of the emergence of resistance against the currently available EGFR inhibitors, our study focuses on tackling this problem through the development of dual EGFR/HER2 inhibitors with improved enzymatic affinities. Guided by the binding mode of the marketed dual EGFR/HER2 inhibitor, Lapatinib, we proposed the design of dual EGFR/HER2 inhibitors based on the 6-phenylthieno[2,3-d]pyrimidine as a core scaffold and hinge binder. After two cycles of screening aiming to identify the optimum aniline headgroup and solubilizing group, we eventually identified 27b as a dual EGFR/HER2 inhibitor with IC 50 values of 91.7 nM and 1.2 μM, respectively. Notably, 27b dramatically reduced the viability of various patient-derived cancer cells preferentially overexpressing EGFR/HER2 (A431, MDA-MBA-361 and SKBr3 with IC 50 values of 1.45, 3.5 and 4.83 μM, respectively). Additionally, 27b efficiently thwarted the proliferation of lapatinib-resistant human non-small lung carcinoma (NCI-H1975) cells, harboring T790 M mutation, with IC 50 of 4.2 μM. Consistently, 27b significantly blocked EGF-induced EGFR activation and inactivated its downstream AKT/mTOR/S6 signalling pathway triggering apoptotic cell death in NCI-H1975 cells. The present study presents a promising candidate for further design and development of novel EGFR/HER2 inhibitors capable of overcoming EGFR TKIs resistance., (Copyright © 2018 Elsevier Masson SAS. All rights reserved.)

• Thieno[2,3- d ]pyrimidine-based dual EGFR/HER2 inhibitors were designed. • 12 compounds were prepared and tested against EGFR, HER2 and T790M/L858R. • Their anti-proliferative activities were assessed against relevant cancer cell lines. EGFR inhibitors have been in clinical use for the treatment of non-small cell lung cancer and breast cancer for years. However, generation after generation of the developed EGFR inhibitors have been met by clinical resistance. In an attempt to develop the next generation of EGFR inhibitors, compound (2) was selected as a lead for optimization. (2) was identified during a previous study for the development of thieno[2,3- d ]pyrimidine-based dual EGFR/HER2 inhibitors where it demonstrated good dual EGFR/HER2 inhibition and selective anti-proliferative activity against the lapatinib-sensitive cancer cell lines. Additionally, it showed modest activity against the T790M/L858R EGFR mutant. Twelve derivatives based on (2) were designed with the aim of optimizing the enzymatic and cellular activity of (2). Those twelve derivatives were prepared and tested for their inhibitory activities against EGFR, HER2 and T790M/L858R, and for their anti-proliferative activity against the cancer cell lines A431 and MDA-MB-468, and the NCI-60 panel of human cancer cell lines. The results provide an insight into the structural features required for EGFR/HER2 inhibition, and the conclusions drawn from this study could help direct future development of EGFR inhibitors that can overcome the current resistance mechanisms. [Display omitted] [ABSTRACT FROM AUTHOR]