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Ref Type Journal Article
PMID (26419724)
Authors Kesarwani M, Huber E, Kincaid Z, Evelyn CR, Biesiada J, Rance M, Thapa MB, Shah NP, Meller J, Zheng Y, Azam M
Title Targeting substrate-site in Jak2 kinase prevents emergence of genetic resistance.
Journal Vol Issue Date Pages Journal Short Title
Scientific reports 5 2015 Sep 30 14538 Sci Rep
URL
Abstract Text Emergence of genetic resistance against kinase inhibitors poses a great challenge for durable therapeutic response. Here, we report a novel mechanism of JAK2 kinase inhibition by fedratinib (TG101348) that prevents emergence of genetic resistance. Using in vitro drug screening, we identified 211 amino-acid substitutions conferring resistance to ruxolitinib (INCB018424) and cross-resistance to the JAK2 inhibitors AZD1480, CYT-387 and lestaurtinib. In contrast, these resistant variants were fully sensitive to fedratinib. Structural modeling, coupled with mutagenesis and biochemical studies, revealed dual binding sites for fedratinib. In vitro binding assays using purified proteins showed strong affinity for the substrate-binding site (Kd = 20 nM) while affinity for the ATP site was poor (Kd = ~8 μM). Our studies demonstrate that mutations affecting the substrate-binding pocket encode a catalytically incompetent kinase, thereby preventing emergence of resistant variants. Most importantly, our data suggest that in order to develop resistance-free kinase inhibitors, the next-generation drug design should target the substrate-binding site.

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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 E987D missense unknown JAK2 E987D lies within protein kinase domain 2 of the Jak2 protein (UniProt.org). E987D has been demonstrated to confer resistance to Jak inhibitors in the context of complex JAK2 mutations (PMID: 26419724), but has not been biochemically characterized and therefore, its effect on Jak2 protein function is unknown (PubMed, Mar 2024). Y
JAK2 F1061W missense unknown JAK2 F1061W lies within protein kinase domain 2 of the Jak2 protein (UniProt.org). F1061W has been demonstrated to confer Jak2 inhibitor resistance in combination with V617F and Y931C in culture (PMID: 26419724), but has not been biochemically characterized and therefore, its effect on Jak2 protein function is unknown (PubMed, Apr 2024). Y
JAK2 G417P missense gain of function - predicted JAK2 G417P lies within the atypical SH2 domain of the Jak2 protein (PMID: 26419724). G417P results in transformation of cells in culture (PMID: 26419724), and therefore, is predicted to lead to a gain of Jak2 protein function.
JAK2 H110R missense gain of function - predicted JAK2 H110R lies within the FERM domain of the Jak2 protein (UniProt.org). H110R results in transformation of cells in culture (PMID: 26419724), and therefore, is predicted to lead to a gain of Jak2 protein function.
JAK2 L983F missense unknown JAK2 L983F lies within the active site of the Jak2 protein (PMID: 26419724). L983F confers resistance to some Jak inhibitors, results in decreased cell proliferation in combination with JAK2 V617F in culture (PMID: 26419724), and is not transforming in culture (PMID: 39091915), but has not been fully biochemically characterized and therefore, its effect on Jak2 protein function is unknown.
JAK2 M483R missense gain of function - predicted JAK2 M483R lies within the atypical SH2 domain of the Jak2 protein (PMID: 26419724). M483R results in transformation of cells in culture (PMID: 26419724), and therefore, is predicted to lead to a gain of Jak2 protein function.
JAK2 N99S missense gain of function - predicted JAK2 N99S lies within the FERM domain of the Jak2 protein (PMID: 26419724). N99S results in transformation of cells in culture (PMID: 26419724), and therefore, is predicted to lead to a gain of Jak2 protein function.
JAK2 P58A missense gain of function - predicted JAK2 P58A lies within the FERM domain of the Jak2 protein (UniProt.org). P58A results in transformation of cells in culture (PMID: 26419724), and therefore, is predicted to lead to a gain of Jak2 protein function.
JAK2 R277K missense gain of function - predicted JAK2 R277K lies within the FERM domain of the Jak2 protein (UniProt.org). R277K results in transformation of cells in culture (PMID: 26419724), and therefore, is predicted to lead to a gain of Jak2 protein function.
JAK2 R683T missense gain of function - predicted JAK2 R683T lies within protein kinase domain 1 of the Jak2 protein (UniProt.org). R683E results in transformation of cells in culture (PMID: 26419724), and therefore, is predicted to lead to a gain of Jak2 protein function.
JAK2 R971G missense unknown JAK2 R971G lies within the activation-loop of the Jak2 protein (PMID: 26419724). R971G confers resistance to some Jak inhibitors, and demonstrates reduced cell proliferation in combination with JAK2 V617F in culture (PMID: 26419724), but has not been individually characterized and therefore, its effect on Jak2 protein function is unknown. Y
JAK2 S1025C missense unknown JAK2 S1025C lies within protein kinase domain 2 of the Jak2 protein (UniProt.org). S1025C has been demonstrated to confer Jak2 inhibitor resistance in combination with V617F and Y931C in culture (PMID: 26419724), but has not been biochemically characterized and therefore, its effect on Jak2 protein function is unknown (PubMed, Apr 2024). Y
JAK2 V1075F missense unknown JAK2 V1075F lies within protein kinase domain 2 of the Jak2 protein (UniProt.org). V1075F has been demonstrated to confer Jak2 inhibitor resistance in combination with V617F and Y931C in culture (PMID: 26419724), but has not been biochemically characterized and therefore, its effect on Jak2 protein function is unknown (PubMed, Apr 2024). Y
JAK2 V366G missense gain of function - predicted JAK2 V366G lies within the FERM domain of the Jak2 protein (UniProt.org). V366G results in transformation of cells in culture (PMID: 26419724), and therefore, is predicted to lead to a gain of Jak2 protein function.
JAK2 Y1045W missense unknown JAK2 Y1045W lies within protein kinase domain 2 of the Jak2 protein (UniProt.org). Y1045W has been demonstrated to confer Jak2 inhibitor resistance in combination with V617F and Y931C in culture (PMID: 26419724), but has not been biochemically characterized and therefore, its effect on Jak2 protein function is unknown (PubMed, Apr 2024). Y
JAK2 Y44C missense gain of function - predicted JAK2 Y44C lies within the FERM domain of the Jak2 protein (UniProt.org). Y44C results in transformation of cells in culture (PMID: 26419724), and therefore, is predicted to lead to a gain of Jak2 protein function.
JAK2 Y931C missense gain of function JAK2 Y931C lies within the protein kinase domain 2 of the Jak2 protein (UniProt.org). Y931C results in increased phosphorylation of Jak2 and Stat5, is transforming in cell culture, and confers resistance to Jak inhibitors (PMID: 21393331, PMID: 26419724). Y
JAK2 Y931F missense unknown JAK2 Y931F lies within protein kinase domain 2 of the Jak2 protein (UniProt.org). Y931F results in Epo-induced activation of Jak2 and colony formation similar to wild-type Jak2 in culture (PMID: 18160720), but is transforming in culture (PMID: 26419724), and therefore, its effect on Jak2 protein function is unknown.
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
JAK2 V617F JAK2 R971G Advanced Solid Tumor resistant Ruxolitinib Preclinical - Cell culture Actionable In a preclinical study, transformed cells expressing JAK2 V617F and R971G demonstrated resistance to Jakafi (Ruxolitinib) in culture (PMID: 26419724). 26419724
JAK2 V617F JAK2 Y931C JAK2 F1061W Advanced Solid Tumor resistant Fedratinib Preclinical - Cell culture Actionable In a preclinical study, transformed cells expressing JAK2 V617F, Y931C and F1061W demonstrated resistance to Inrebic (fedratinib) treatment in culture (PMID: 26419724). 26419724
JAK2 V617F JAK2 Y931C JAK2 S1025C Advanced Solid Tumor resistant Fedratinib Preclinical - Cell culture Actionable In a preclinical study, transformed cells expressing JAK2 V617F, Y931C and S1025C demonstrated resistance to Inrebic (fedratinib) treatment in culture (PMID: 26419724). 26419724
JAK2 V617F JAK2 L983F Advanced Solid Tumor resistant Ruxolitinib Preclinical Actionable In a preclinical study, transformed cells expressing JAK2 V617F and L983F demonstrated resistance to Jakafi (Ruxolitinib) treatment in cell culture and in a syngeneic mouse model (PMID: 26419724). 26419724
JAK2 V617F JAK2 Y931C JAK2 V1075F Advanced Solid Tumor resistant Fedratinib Preclinical - Cell culture Actionable In a preclinical study, transformed cells expressing JAK2 V617F, Y931C and V1075F demonstrated resistance to Inrebic (fedratinib) treatment in culture (PMID: 26419724). 26419724
JAK2 V617F JAK2 Y931C Advanced Solid Tumor sensitive Fedratinib Preclinical - Cell culture Actionable In a preclinical study, Inrebic (fedratinib) treatment inhibited colony formation and proliferation of transformed cells expressing JAK2 V617F and Y931C in culture (PMID: 26419724). 26419724
JAK2 V617F JAK2 E987D Advanced Solid Tumor resistant Ruxolitinib Preclinical - Cell culture Actionable In a preclinical study, transformed cells expressing JAK2 V617F and E987D demonstrated resistance to Jakafi (Ruxolitinib) treatment in culture (PMID: 26419724). 26419724
JAK2 V617F JAK2 Y931C JAK2 Y1045W Advanced Solid Tumor resistant Fedratinib Preclinical - Cell culture Actionable In a preclinical study, transformed cells expressing JAK2 V617F, Y931C and Y1045W demonstrated resistance to Inrebic (fedratinib) treatment in culture (PMID: 26419724). 26419724