1. New scaffolds for type II JAK2 inhibitors overcome the acquired G993A resistance mutation.
- Author
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Arwood ML, Liu Y, Harkins SK, Weinstock DM, Yang L, Stevenson KE, Plana OD, Dong J, Cirka H, Jones KL, Virtanen AT, Gupta DG, Ceas A, Lawney B, Yoda A, Leahy C, Hao M, He Z, Choi HG, Wang Y, Silvennoinen O, Hubbard SR, Zhang T, Gray NS, and Li LS
- Subjects
- Humans, Mutation, Janus Kinase 2 genetics, Janus Kinase 2 metabolism, Myeloproliferative Disorders genetics
- Abstract
Recurrent JAK2 alterations are observed in myeloproliferative neoplasms, B-cell acute lymphoblastic leukemia, and other hematologic malignancies. Currently available type I JAK2 inhibitors have limited activity in these diseases. Preclinical data support the improved efficacy of type II JAK2 inhibitors, which lock the kinase in the inactive conformation. By screening small molecule libraries, we identified a lead compound with JAK2 selectivity. We highlight analogs with on-target biochemical and cellular activity and demonstrate in vivo activity using a mouse model of polycythemia vera. We present a co-crystal structure that confirms the type II binding mode of our compounds with the "DFG-out" conformation of the JAK2 activation loop. Finally, we identify a JAK2 G993A mutation that confers resistance to the type II JAK2 inhibitor CHZ868 but not to our analogs. These data provide a template for identifying novel type II kinase inhibitors and inform further development of agents targeting JAK2 that overcome resistance., Competing Interests: Declaration of interests S.R.H. and O.S. are co-founders, equity holders, and scientific advisory board members of Ajax Therapeutics, Inc. N.S.G. is a founder, science advisory board member (SAB) and equity holder in Syros, C4, Allorion, Lighthorse, Voronoi, Inception, Matchpoint, CobroVentures, GSK, Larkspur (board member), and Soltego (board member). T.Z. is a founder, equity holder, and consultant for Matchpoint. The Gray lab receives or has received research funding from Novartis, Takeda, Astellas, Taiho, Jansen, Kinogen, Arbella, Deerfield, Springworks, Interline, and Sanofi. D.M.W. is an employee of Merck and co-founder and equity holder of Ajax Therapeutics, Inc. and Travera. D.M.W. is an advisor or consultant for Bantam, Ajax Therapeutics, Inc., Secura, Travera, AstraZeneca, and Daiichi Sankyo. The Weinstock lab has received research support from Daiichi Sankyo, Verastem, Secura, and Abcuro. T.Z., Y.L., Z.H., M.H., N.S.G., D.M.W., and L.S.L. are co-inventors on patent number WO 2020/097400 A1 related to this work. K.E.S. is now an employee of Novartis and K.L.J. is now an employee of AstraZeneca., (Copyright © 2023 Elsevier Ltd. All rights reserved.)
- Published
- 2023
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