Structure-Based Optimization of Pyrazinamide-Containing Macrocyclic Derivatives As Fms-like Tyrosine Kinase 3 (FLT3) Inhibitors to Overcome Clinical Mutations

Overview

Journal ACS Pharmacol Transl Sci

Publisher American Chemical Society

Specialty Biochemistry

Date 2024 May 16

PMID 38751627

Authors

Xuan Zheng

Zhiwen Chen

Ming Guo

Hong Liang

Xiaojuan Song

Yiling Liu

Zhenling Liao

Yan Zhang

Jing Guo

Yang Zhou

Zhi-Min Zhang

Zhengchao Tu

Ye Zhang

Yongheng Chen

Zhang Zhang

Xiaoyun Lu

Affiliations

Soon will be listed here.

Abstract

Secondary mutations in Fms-like tyrosine kinase 3-tyrosine kinase domain (FLT3-TKD) (e.g., D835Y and F691L) have become a major on-target resistance mechanism of FLT3 inhibitors, which present a significant clinical challenge. To date, no effective drugs have been approved to simultaneously overcome clinical resistance caused by these two mutants. Thus, a series of pyrazinamide macrocyclic compounds were first designed and evaluated to overcome the secondary mutations of FLT3. The representative exhibited potent inhibitory activities against FLT3 and FLT3 with IC values of 1.5 and 9.7 nM, respectively. also strongly suppressed the proliferation against Ba/F3 cells transfected with FLT3-ITD, FLT3-ITD-D835Y, FLT3-ITD-F691L, FLT3-ITD-D835Y-F691L, and MV4-11 acute myeloid leukemia (AML) cell lines with IC values of 12.2, 10.5, 24.6, 16.9, and 6.8 nM, respectively. Furthermore, demonstrated ideal anticancer efficacy in a Ba/F3-FLT3-ITD-D835Y xenograft model. The results suggested that can serve as a promising macrocycle-based FLT3 inhibitor for the treatment of AML.

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