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Ref Type Journal Article
PMID (29927999)
Authors Koblish H, Li YL, Shin N, Hall L, Wang Q, Wang K, Covington M, Marando C, Bowman K, Boer J, Burke K, Wynn R, Margulis A, Reuther GW, Lambert QT, Dostalik Roman V, Zhang K, Feng H, Xue CB, Diamond S, Hollis G, Yeleswaram S, Yao W, Huber R, Vaddi K, Scherle P
Title Preclinical characterization of INCB053914, a novel pan-PIM kinase inhibitor, alone and in combination with anticancer agents, in models of hematologic malignancies.
Journal PloS one
Vol 13
Issue 6
Date 2018
URL
Abstract Text The Proviral Integration site of Moloney murine leukemia virus (PIM) serine/threonine protein kinases are overexpressed in many hematologic and solid tumor malignancies and play central roles in intracellular signaling networks important in tumorigenesis, including the Janus kinase-signal transducer and activator of transcription (JAK/STAT) and phosphatidylinositol 3-kinase (PI3K)/AKT pathways. The three PIM kinase isozymes (PIM1, PIM2, and PIM3) share similar downstream substrates with other key oncogenic kinases and have differing but mutually compensatory functions across tumors. This supports the therapeutic potential of pan-PIM kinase inhibitors, especially in combination with other anticancer agents chosen based on their role in overlapping signaling networks. Reported here is a preclinical characterization of INCB053914, a novel, potent, and selective adenosine triphosphate-competitive pan-PIM kinase inhibitor. In vitro, INCB053914 inhibited proliferation and the phosphorylation of downstream substrates in cell lines from multiple hematologic malignancies. Effects were confirmed in primary bone marrow blasts from patients with acute myeloid leukemia treated ex vivo and in blood samples from patients receiving INCB053914 in an ongoing phase 1 dose-escalation study. In vivo, single-agent INCB053914 inhibited Bcl-2-associated death promoter protein phosphorylation and dose-dependently inhibited tumor growth in acute myeloid leukemia and multiple myeloma xenografts. Additive or synergistic inhibition of tumor growth was observed when INCB053914 was combined with selective PI3Kδ inhibition, selective JAK1 or JAK1/2 inhibition, or cytarabine. Based on these data, pan-PIM kinase inhibitors, including INCB053914, may have therapeutic utility in hematologic malignancies when combined with other inhibitors of oncogenic kinases or standard chemotherapeutics.

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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
INCB053914 INCB53914 PIM Inhibitor (Pan) 9 INCB053914 is an ATP-competitive small molecule inhibitor of PIM kinases 1, 2, and 3, which may inhibit cell proliferation by blocking the phosphorylation of downstream targets (PMID: 29927999, PMID: 31725895).
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
JAK2 V617F essential thrombocythemia predicted - sensitive INCB053914 Preclinical - Patient cell culture Actionable In a preclinical study, INCB053914 inhibited erythroid colony formation in cells derived from patient with myeloproliferative neoplasms (MPNs), including essential thrombocythemia, harboring JAK2 V617F in culture (PMID: 29927999). 29927999
JAK2 V617F myelofibrosis predicted - sensitive INCB053914 Preclinical - Patient cell culture Actionable In a preclinical study, INCB053914 inhibited erythroid colony formation in cells derived from patients with myeloproliferative neoplasms (MPNs), including primary myelofibrosis, harboring JAK2 V617F in culture (PMID: 29927999). 29927999
JAK2 V617F polycythemia vera predicted - sensitive INCB053914 Preclinical - Patient cell culture Actionable In a preclinical study, INCB053914 inhibited erythroid colony formation in cells derived from patients with myeloproliferative neoplasms, including polycythemia vera, harboring JAK2 V617F in culture (PMID: 29927999). 29927999