M. E. Dokla, E, Kamal Abdel-Aziz, A, Milik, SN et al. (3 more authors) (2022) Discovery of a Benzimidazole-based Dual FLT3/TrKA Inhibitor Targeting Acute Myeloid Leukemia. Bioorganic and Medicinal Chemistry, 56. 116596. p. 116596. ISSN 0968-0896
Abstract
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 (IC50 = 43.8, 97.2, and 92.5 nM respectively). Additionally, 4ACP demonstrated potent activity against colon cancer KM12 cell line (IC50 = 358 nM) and subsequent mechanistic deconvolution identified TrKA enzyme as a second plausible target (IC50 = 23.6 nM) for our compound. 4ACP manifested preferential antiproliferative activity against FLT3-ITD positive AML cell lines (MV4-11 IC50 = 38.8 ± 10.7 nM and MOLM-13 IC50 = 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.
Metadata
Item Type: | Article |
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Authors/Creators: |
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Copyright, Publisher and Additional Information: | © 2021 Elsevier Ltd. All rights reserved. This is an author produced version of an article, published in Bioorganic and Medicinal Chemistry. Uploaded in accordance with the publisher's self-archiving policy. |
Keywords: | FLT3; TrKA; Dual kinase inhibitor; Acute myeloid leukemia; Benzimidazole; Scaffold hopping |
Dates: |
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Institution: | The University of Leeds |
Academic Units: | The University of Leeds > Faculty of Engineering & Physical Sciences (Leeds) > School of Chemistry (Leeds) > Organic Chemistry (Leeds) |
Depositing User: | Symplectic Publications |
Date Deposited: | 17 Jan 2022 10:08 |
Last Modified: | 30 Dec 2022 01:13 |
Status: | Published |
Publisher: | Elsevier |
Identification Number: | 10.1016/j.bmc.2021.116596 |
Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:182443 |