Discovery of imidazo[1,2-a]pyridine-thiophene derivatives as FLT3 and FLT3 mutants inhibitors for acute myeloid leukemia through structure-based optimization of an NEK2 inhibitor

Lingtian Zhang, Naga Rajiv Lakkaniga, Jaideep B. Bharate, Nicholas Mcconnell, Xiuqi Wang, Anupreet Kharbanda, Yuet Kin Leung, Brendan Frett, Neil P. Shah, Hong yu Li

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

Abstract

FMS-like tyrosine kinase 3 (FLT3) with an internal tandem duplication (ITD) mutation has been validated as a driver lesion and a therapeutic target for acute myeloid leukemia (AML). Currently, several potent small-molecule FLT3 kinase inhibitors are being evaluated or have completed evaluation in clinical trials. However, many of these inhibitors are challenged by the secondary mutations on kinase domain, especially the point mutations at the activation loop (D835) and gatekeeper residue (F691). To overcome the resistance challenge, we identified a novel series of imidazo[1,2-a]pyridine-thiophene derivatives from a NIMA-related kinase 2 (NEK2) kinase inhibitor CMP3a, which retained inhibitory activities on FTL3-ITDD835V and FLT3-ITDF691L. Through this study, we identified the imidazo[1,2-a]pyridine-thiophene derivatives as type-I inhibitors of FLT3. Moreover, we observed compound 5o as an inhibitor displaying equal anti-proliferative activities against FLT3-ITD, FTL3-ITDD835Y and FLT3-ITDF691L driven acute myeloid leukemia (AML) cell lines. Meanwhile, the apoptotic effects of compound supported its mechanism of anti-proliferative action. These results indicate that the imidazo[1,2-a]pyridine-thiophene scaffold is promising for targeting acquired resistance caused by FLT3 secondary mutations and compound 5o is an interesting lead in this direction.

Original languageEnglish (US)
Article number113776
JournalEuropean journal of medicinal chemistry
Volume225
DOIs
StatePublished - Dec 5 2021

Keywords

  • AML
  • FLT3
  • Imidazole pyridine
  • Mutants

ASJC Scopus subject areas

  • Pharmacology
  • Drug Discovery
  • Organic Chemistry

Fingerprint

Dive into the research topics of 'Discovery of imidazo[1,2-a]pyridine-thiophene derivatives as FLT3 and FLT3 mutants inhibitors for acute myeloid leukemia through structure-based optimization of an NEK2 inhibitor'. Together they form a unique fingerprint.

Cite this