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

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

doi:10.1021/acsptsci.4c00071

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

ACS Pharmacol Transl Sci. 2024 Apr 11;7(5):1485-1506. doi: 10.1021/acsptsci.4c00071. eCollection 2024 May 10.

Authors

Xuan Zheng¹, Zhiwen Chen¹, Ming Guo², Hong Liang¹, Xiaojuan Song¹, Yiling Liu¹, Zhenling Liao¹, Yan Zhang¹, Jing Guo¹, Yang Zhou¹, Zhi-Min Zhang¹, Zhengchao Tu¹, Ye Zhang³, Yongheng Chen², Zhang Zhang¹, Xiaoyun Lu^{1

4}

Affiliations

¹ State Key Laboratory of Bioactive Molecules and Druggability Assessment, International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Discovery of Chinese Ministry of Education, Guangzhou City Key Laboratory of Precision Chemical Drug Development, School of Pharmacy, Jinan University, #855 Xingye Avenue, Guangzhou 510632, China.
² Department of Oncology, NHC Key Laboratory of Cancer Proteomics, State Local Joint Engineering Laboratory for Anticancer Drugs, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China.
³ Guangxi Key Laboratory of Drug Discovery and Optimization, School of Pharmacy, Guilin Medical University, Guilin 541199, China.
⁴ Department of Hematology, Guangdong Second Provincial General Hospital, Jinan University, Guangzhou 510632, China.

PMID: 38751627
PMCID: PMC11092118 (available on 2025-04-11)
DOI: 10.1021/acsptsci.4c00071

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 8v exhibited potent inhibitory activities against FLT3^D835Y and FLT3^D835Y/F691L with IC₅₀ values of 1.5 and 9.7 nM, respectively. 8v 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 IC₅₀ values of 12.2, 10.5, 24.6, 16.9, and 6.8 nM, respectively. Furthermore, 8v demonstrated ideal anticancer efficacy in a Ba/F3-FLT3-ITD-D835Y xenograft model. The results suggested that 8v can serve as a promising macrocycle-based FLT3 inhibitor for the treatment of AML.