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Ref Type Journal Article
PMID (37290440)
Authors 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, Li LS
Title New scaffolds for type II JAK2 inhibitors overcome the acquired G993A resistance mutation.
Journal Vol Issue Date Pages Journal Short Title
Cell chemical biology 30 6 2023 Jun 15 618-631.e12 Cell Chem Biol
URL
Abstract Text 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.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
JAK2 G993A missense unknown JAK2 G993A lies within protein kinase domain 2 of the Jak2 protein (UniProt.org). G993A has been demonstrated to occur as a secondary drug resistance mutation in the context of activating JAK2 mutations in cultured cells (PMID: 34376782, PMID: 37290440), and is not transforming in culture (PMID: 34376782), but has not been fully biochemically characterized and therefore, its effect on Jak2 protein function is unknown. Y
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
JAK2 V617F JAK2 G993A Advanced Solid Tumor resistant CHZ868 Preclinical - Cell culture Actionable In a preclinical study, a cell line expressing JAK2 V617F and G993A was resistant to CHZ868 in culture (PMID: 37290440). 37290440
JAK2 V617F JAK2 G993A Advanced Solid Tumor resistant Ruxolitinib Preclinical - Cell culture Actionable In a preclinical study, a cell line expressing JAK2 V617F and G993A was resistant to Jakafi (ruxolitinib) in culture (PMID: 37290440). 37290440
JAK2 R683G Advanced Solid Tumor sensitive CHZ868 Preclinical - Cell culture Actionable In a preclinical study, CHZ868 inhibited viability of a cell line expressing JAK2 R683G in culture (PMID: 37290440). 37290440
JAK2 R683G JAK2 L884P Advanced Solid Tumor sensitive Ruxolitinib Preclinical - Cell culture Actionable In a preclinical study, Jakafi (ruxolitinib) inhibited viability of a cell line expressing JAK2 R683G and L884P in culture (PMID: 37290440). 37290440
JAK2 V617F Advanced Solid Tumor sensitive CHZ868 Preclinical - Cell culture Actionable In a preclinical study, CHZ868 inhibited viability of a cell line expressing JAK2 V617F in culture (PMID: 37290440). 37290440
JAK2 R683G JAK2 L884P Advanced Solid Tumor sensitive Fedratinib Preclinical - Cell culture Actionable In a preclinical study, Inrebic (fedratinib) inhibited viability of a cell line expressing JAK2 R683G and L884P in culture (PMID: 37290440). 37290440
JAK2 R683G JAK2 G993A Advanced Solid Tumor resistant CHZ868 Preclinical - Cell culture Actionable In a preclinical study, a cell line expressing JAK2 R683G and G993A was resistant to CHZ868 in culture (PMID: 37290440). 37290440
JAK2 R683G JAK2 G993A Advanced Solid Tumor resistant Ruxolitinib Preclinical - Cell culture Actionable In a preclinical study, a cell line expressing JAK2 R683G and G993A was resistant to Jakafi (ruxolitinib) in culture (PMID: 37290440). 37290440