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Design, synthesis and structure-activity relationship studies of pyrido[2,3-d]pyrimidin-7-ones as potent Janus Kinase 3 (JAK3) covalent inhibitors. 2022

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

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.

UI MeSH Term Description Entries
D013329 Structure-Activity Relationship The relationship between the chemical structure of a compound and its biological or pharmacological activity. Compounds are often classed together because they have structural characteristics in common including shape, size, stereochemical arrangement, and distribution of functional groups. Relationship, Structure-Activity,Relationships, Structure-Activity,Structure Activity Relationship,Structure-Activity Relationships
D047428 Protein Kinase Inhibitors Agents that inhibit PROTEIN KINASES. Protein Kinase Inhibitor,Inhibitor, Protein Kinase,Inhibitors, Protein Kinase,Kinase Inhibitor, Protein,Kinase Inhibitors, Protein
D053613 Janus Kinase 1 A Janus kinase subtype that is involved in signaling from a broad variety of CYTOKINE RECEPTORS. JAK-1 Protein Tyrosine Kinase,JAK1 Protein Tyrosine Kinase,Jak1 Kinase,JAK 1 Protein Tyrosine Kinase
D053614 Janus Kinase 2 A Janus kinase subtype that is involved in signaling from GROWTH HORMONE RECEPTORS; PROLACTIN RECEPTORS; and a variety of CYTOKINE RECEPTORS such as ERYTHROPOIETIN RECEPTORS and INTERLEUKIN RECEPTORS. Dysregulation of Janus kinase 2 due to GENETIC TRANSLOCATIONS have been associated with a variety of MYELOPROLIFERATIVE DISORDERS. JAK-2 Protein Tyrosine Kinase,JAK2 Protein Tyrosine Kinase,JAK 2 Protein Tyrosine Kinase
D053616 Janus Kinase 3 A Janus kinase subtype that is predominantly expressed in hematopoietic cells. It is involved in signaling from a broad variety of CYTOKINE RECEPTORS including ones that utilize the INTERLEUKIN RECEPTOR COMMON GAMMA SUBUNIT. JAK-3 Protein Tyrosine Kinase,JAK3 Protein Tyrosine Kinase,JAK 3 Protein Tyrosine Kinase,Kinase 3, Janus

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