Journal
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
Volume 64, Issue -, Pages -Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmcl.2022.128680
Keywords
JAK3; Covalent inhibitor; Anti-cancer activity; Selectivity
Categories
Funding
- Shanghai Pujiang Program [19PJ1411400]
- National Ministry of Science and Technology [SQ2019YFE010401]
- Na-tional Natural Science Foundation of China [81973158]
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This study presents a new series of JAK3 covalent inhibitors and identifies compound 10f as the most potent inhibitor with high selectivity and inhibitory activity against JAK3. It may serve as a promising tool molecule for treating cancers with aberrantly activated JAK3.
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.& nbsp;
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