Reference Detail

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	Vol	Issue	Date	Pages	Journal Short Title
PloS one	13	6	2018	e0199108	PLoS One

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
INCB053914	INCB053914	3	1

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	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
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	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