Design, synthesis and structure-activity relationship studies of pyrido[2,3-d]pyrimidin-7-ones as potent Janus Kinase 3 (JAK3) covalent inhibitors

Wenhong Su; Zhiwen Chen; Meiying Liu; Rui He; Chaoyi Liu; Rui Li; Mingshan Gao; Mingyue Zheng; Zhengchao Tu; Zhang Zhang; Tianfeng Xu

doi:10.1016/j.bmcl.2022.128680

Design, synthesis and structure-activity relationship studies of pyrido[2,3-d]pyrimidin-7-ones as potent Janus Kinase 3 (JAK3) covalent inhibitors

Bioorg Med Chem Lett. 2022 May 15:64:128680. doi: 10.1016/j.bmcl.2022.128680. Epub 2022 Mar 16.

Authors

Wenhong Su¹, Zhiwen Chen², Meiying Liu³, Rui He², Chaoyi Liu³, Rui Li⁴, Mingshan Gao³, Mingyue Zheng⁴, Zhengchao Tu⁵, Zhang Zhang⁶, Tianfeng Xu⁷

Affiliations

¹ Department of Medicinal Chemistry, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China; Nano Science and Technology Institute, University of Science and Technology of China, Suzhou 215123, China.
² International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Development, Ministry of Education (MoE) of People's Republic of China, College of Pharmacy, Jinan University, 601 Huangpu Avenue West, Guangzhou 510632, China.
³ Department of Medicinal Chemistry, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China.
⁴ Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China.
⁵ Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, 190 Kaiyuan Avenue, Guangzhou Science Park, Guangzhou 510530, China.
⁶ International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Development, Ministry of Education (MoE) of People's Republic of China, College of Pharmacy, Jinan University, 601 Huangpu Avenue West, Guangzhou 510632, China. Electronic address: zhang_zhang@jnu.edu.cn.
⁷ Department of Medicinal Chemistry, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China; School of Pharmaceutical Science and Technology, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou 310024, China. Electronic address: tfxu@simm.ac.cn.

PMID: 35306167
DOI: 10.1016/j.bmcl.2022.128680

Abstract

Aberrantly activated Janus kinase 3 (JAK3) has been constantly detected in various immune disorders and hematopoietic cancers, suggesting its potential of being an attractive therapeutic target for these indications. Clinical benefits of drugs selectively targeting JAK3 versus pan-JAK inhibitors remain unclear. In this study, we report the design and synthesis of a new series of JAK3 covalent inhibitors with a pyrido[2,3-d]pyrimidin-7-one scaffold. After the extensive SAR study, compound 10f emerged to be the most potent JAK3 inhibitor with an IC₅₀ value of 2.0 nM. It showed excellent selectively proliferation inhibitory activity against U937 cells harboring JAK3 M511I mutation, while remained weakly active to the other tested cancer cells. Compound 10f also dose-dependently inhibited the phosphorylation of JAK3 and its downstream signal STAT5 in U937 cells. Taken together, 10f may serve as a promising tool molecule for treating cancers with aberrantly activated JAK3.

Keywords: Anti-cancer activity; Covalent inhibitor; JAK3; Selectivity.

Publication types

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

MeSH terms

Janus Kinase 1
Janus Kinase 2
Janus Kinase 3* / metabolism
Protein Kinase Inhibitors* / pharmacology
Structure-Activity Relationship

Substances

Protein Kinase Inhibitors
Janus Kinase 1
Janus Kinase 2
Janus Kinase 3