2. Academic Validation
  3. Discovery of a benzimidazole-based dual FLT3/TrKA inhibitor targeting acute myeloid leukemia

Discovery of a benzimidazole-based dual FLT3/TrKA inhibitor targeting acute myeloid leukemia

  • Bioorg Med Chem. 2022 Feb 15;56:116596. doi: 10.1016/j.bmc.2021.116596.
Eman M E Dokla 1,  Amal Kamal Abdel-Aziz 2,  Sandra N Milik 3,  Martin J McPhillie 4,  Saverio Minucci 5,  Khaled A M Abouzid 6
Affiliations

Affiliations

  • 1 Pharmaceutical Chemistry Department, Faculty of Pharmacy, Ain Shams University, Abbassia, Cairo 11566, Egypt. Electronic address: emanelawady@pharma.asu.edu.eg.
  • 2 Department of Pharmacology and Toxicology, Faculty of Pharmacy, Ain Shams University, Abbassia, Cairo 11566, Egypt; Department of Experimental Oncology, IEO, European Institute of Oncology IRCCS, Via Adamello 16, 20139 Milan, Italy.
  • 3 Pharmaceutical Chemistry Department, Faculty of Pharmacy, Ain Shams University, Abbassia, Cairo 11566, Egypt; School of Chemistry, University of Leeds, Leeds LS2 9JT, United Kingdom.
  • 4 School of Chemistry, University of Leeds, Leeds LS2 9JT, United Kingdom.
  • 5 Department of Experimental Oncology, IEO, European Institute of Oncology IRCCS, Via Adamello 16, 20139 Milan, Italy; Department of Biosciences, University of Milan, Milan 20100, Italy. Electronic address: Saverio.Minucci@ieo.it.
  • 6 Pharmaceutical Chemistry Department, Faculty of Pharmacy, Ain Shams University, Abbassia, Cairo 11566, Egypt; Department of Organic and Medicinal Chemistry, Faculty of Pharmacy, University of Sadat City, Sadat City 32897, Egypt.
PMID: 35033885 DOI: 10.1016/j.bmc.2021.116596
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.

Keywords

Acute myeloid leukemia; Benzimidazole; Dual kinase inhibitor; FLT3; Scaffold hopping; TrKA.

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