Discovery of LWY713 as a potent and selective FLT3 PROTAC degrader with in vivo activity against acute myeloid leukemia

Wenyan Liu; Yu Bai; Licheng Zhou; Jian Jin; Meiying Zhang; Yongxing Wang; Runfeng Lin; Weixue Huang; Xiaomei Ren; Nan Ma; Fengtao Zhou; Zhen Wang; Ke Ding

doi:10.1016/j.ejmech.2023.115974

Discovery of LWY713 as a potent and selective FLT3 PROTAC degrader with in vivo activity against acute myeloid leukemia

Eur J Med Chem. 2024 Jan 15:264:115974. doi: 10.1016/j.ejmech.2023.115974. Epub 2023 Nov 19.

Authors

Wenyan Liu¹, Yu Bai¹, Licheng Zhou², Jian Jin¹, Meiying Zhang¹, Yongxing Wang³, Runfeng Lin³, Weixue Huang¹, Xiaomei Ren¹, Nan Ma², Fengtao Zhou², Zhen Wang¹, Ke Ding⁴

Affiliations

¹ State Key Laboratory of Chemical Biology, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, #345 Lingling Rd., Shanghai, 200032, China.
² International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Discovery of Chinese Ministry of Education (MOE), Guangzhou City Key Laboratory of Precision Chemical Drug Development, College of Pharmacy, Jinan University, 855 Xingye Avenue East, Guangzhou, 511400, China.
³ Livzon Research Institute, Livzon Pharmaceutical Group Inc., #38 Chuangye North Road, Jinwan District, Zhuhai, 519000, China.
⁴ State Key Laboratory of Chemical Biology, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, #345 Lingling Rd., Shanghai, 200032, China; International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Discovery of Chinese Ministry of Education (MOE), Guangzhou City Key Laboratory of Precision Chemical Drug Development, College of Pharmacy, Jinan University, 855 Xingye Avenue East, Guangzhou, 511400, China; Institute of Basic Medicine and Cancer (IBMC), Chinese Academy of Sciences, Hangzhou, Zhejiang, 310022, China. Electronic address: dingk@sioc.ac.cn.

PMID: 38007910
DOI: 10.1016/j.ejmech.2023.115974

Abstract

Fms-like tyrosine kinase 3 (FLT3) has been validated as a therapeutic target for acute myeloid leukemia (AML). While a number of FLT3 kinase inhibitors have been approved for AML treatment, the clinical data revealed that they cannot achieve complete and sustained suppression of FLT3 signaling at the tolerated dose. Here we report a series of new, potent and selective FLT3 proteolysis targeting chimera degraders. The optimal compound LWY713 potently induced the degradation of FLT3 with a DC₅₀ value of 0.64 nM and a D_max value of 94.8% in AML MV4-11 cells with FLT3-internal tandem duplication (ITD) mutation. Mechanistic studies demonstrated that LWY713 selectively induced FLT3 degradation in a cereblon- and proteasome-dependent manner. LWY713 potently inhibited FLT3 signaling, suppressed cell proliferation, and induced cell G0/G1-phase arrest and apoptosis in MV4-11 cells. Importantly, LWY713 displayed potent in vivo antitumor activity in MV4-11 xenograft models.

Keywords: Acute myeloid leukemia; Antitumor activity; Degrader; FLT3; Proteolysis targeting chimera.

MeSH terms

Apoptosis
Cell Line, Tumor
Cell Proliferation
Humans
Leukemia, Myeloid, Acute* / pathology
Mutation
Protein Kinase Inhibitors / pharmacology
Protein Kinase Inhibitors / therapeutic use
fms-Like Tyrosine Kinase 3* / genetics

Substances

fms-Like Tyrosine Kinase 3
Protein Kinase Inhibitors
FLT3 protein, human