卓金聪, Yunlong Li, Ding‐Quan Qian, David Burns, 宋梅, Maria Rafalski, Meizhong Xu, Ganfeng Cao, Yongchun Pan, Zhongjiang Jia, Ravi Jalluri, L.B. Epling, Gustavo Fenalti, Marc C. Deller, Jessica Procak, M.B. Covington, Xin He, Robert Collins, Matthew Stubbs, Krista Burke, Julian Oliver, Alex Margulis, Jason Boer, Richard Wynn, Peggy Scherle, Sharon Diamond, Robert Newton, Yan Zhang, B.L. Metcalf, Wenqing Yao
Abstract Aberrant JAK2 signaling is a key driver in cancers such as myeloproliferative neoplasms (MPNs), whereas JAK1 acts as a central mediator of autoimmune and inflammatory diseases. Since JAK2 supports blood cell production, its inhibition can lead to anemia and other cytopenias, making selective JAK1 inhibition a potentially safer therapeutic strategy opposed to dual JAK1/JAK2 inhibition. We initially identified novel scaffold 9, which selectively inhibited JAK1 over JAK2. Iterative breakthroughs led to the discovery of povorcitinib (INCB054707, 22), which showed improved pharmacokinetics due to intramolecular hydrogen bonding of the amide moiety and a reduced ring size in the hinge binding motif. Protein crystallography suggested that JAK1 selectivity was conferred by the amide’s alkyl group accessing a small lipophilic groove formed by the P-loop conformation of JAK1 that was distinct from JAK2. In murine arthritis models, povorcitinib demonstrated dose-dependent efficacy and reduced inflammatory signaling, supporting its therapeutic potential in immunological disorders.