Design, synthesis, and evaluation of pyrido.[3,4-b]pyrazin-2(1H)-one derivatives as potent FLT3 inhibitors

Mei Sun; Chang Wang; Peipei Wang; Qingqing Ye; Yubo Zhou; Jia Li; Tao Liu

doi:10.1016/j.bmc.2023.117155

Design, synthesis, and evaluation of pyrido.[3,4-b]pyrazin-2(1H)-one derivatives as potent FLT3 inhibitors

Bioorg Med Chem. 2023 Feb 1:79:117155. doi: 10.1016/j.bmc.2023.117155. Epub 2023 Jan 7.

Authors

Mei Sun¹, Chang Wang², Peipei Wang³, Qingqing Ye¹, Yubo Zhou⁴, Jia Li⁵, Tao Liu⁶

Affiliations

¹ ZJU-ENS Joint Laboratory of Medicinal Chemistry, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China.
² National Center for Drug Screening, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
³ School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing 210023, China.
⁴ National Center for Drug Screening, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China; Shandong Laboratory of Yantai Drug Discovery, Bohai Rim Advanced Research Institute for Drug Discovery, Yantai, Shandong 264117, China. Electronic address: ybzhou@mail.shcnc.ac.cn.
⁵ National Center for Drug Screening, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China; School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing 210023, China; Shandong Laboratory of Yantai Drug Discovery, Bohai Rim Advanced Research Institute for Drug Discovery, Yantai, Shandong 264117, China. Electronic address: jli@simm.ac.cn.
⁶ ZJU-ENS Joint Laboratory of Medicinal Chemistry, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China. Electronic address: lt601@zju.edu.cn.

PMID: 36638621
DOI: 10.1016/j.bmc.2023.117155

Abstract

Acute myeloid leukemia (AML) is characterized by fast progression and low survival rates, in which Fms-like tyrosine kinase 3 (FLT3) receptor mutations have been identified as driver mutations in a subgroup of AML patients. Herein, we describe the design, synthesis, and biological evaluation of a novel series of potent pyrido.[3,4-b]pyrazin-2(1H)-one derivatives as FLT3 inhibitors. The compounds exhibited moderate to potent FLT3 kinase inhibitory potency and excellent antiproliferative activities against MV4-11 cells. Among them, compound 13 demonstrated the most potent kinase activity against FLT3-D835Y (IC₅₀ = 29.54 ± 4.76 nM) and cellular potency against MV4-11 cells (IC₅₀ = 15.77 ± 0.15 nM). Compound 13 also efficiently inhibited the growth of multiple mutant BaF3 cells expressing FLT3-D835V/F, FLT3-F691L, and FLT3-ITD/D835Y. Furthermore, compound 13 was metabolically stable in mouse liver microsomes. Moreover, the treatment with compound 13 led to robust inhibition of FLT3 autophosphorylation on Tyr589/591 in MV4-11 cells. In summary, our data demonstrated that 13 was worthy of further study for the treatment of AML.

Keywords: Acute myeloid leukemia; FLT3; FLT3-D835Y; Structure-activity relationships.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Antineoplastic Agents*
Apoptosis
Cell Line, Tumor
Cell Proliferation
Leukemia, Myeloid, Acute* / drug therapy
Mice
Microsomes, Liver
Mutation
Protein Kinase Inhibitors
fms-Like Tyrosine Kinase 3 / genetics

Substances

Antineoplastic Agents
fms-Like Tyrosine Kinase 3
Protein Kinase Inhibitors
pyrido(3,4-b)pyrazin-2(1H)-one