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Ref Type Journal Article
PMID (24474669)
Authors Garcia PD, Langowski JL, Wang Y, Chen M, Castillo J, Fanton C, Ison M, Zavorotinskaya T, Dai Y, Lu J, Niu XH, Basham S, Chan J, Yu J, Doyle M, Feucht P, Warne R, Narberes J, Tsang T, Fritsch C, Kauffmann A, Pfister E, Drueckes P, Trappe J, Wilson C, Han W, Lan J, Nishiguchi G, Lindvall M, Bellamacina C, Aycinena JA, Zang R, Holash J, Burger MT
Title Pan-PIM kinase inhibition provides a novel therapy for treating hematologic cancers.
Journal Clinical cancer research : an official journal of the American Association for Cancer Research
Vol 20
Issue 7
Date 2014 Apr 01
URL
Abstract Text PIM kinases have been shown to act as oncogenes in mice, with each family member being able to drive progression of hematologic cancers. Consistent with this, we found that PIMs are highly expressed in human hematologic cancers and show that each isoform has a distinct expression pattern among disease subtypes. This suggests that inhibitors of all three PIMs would be effective in treating multiple hematologic malignancies.Pan-PIM inhibitors have proven difficult to develop because PIM2 has a low Km for ATP and, thus, requires a very potent inhibitor to effectively block the kinase activity at the ATP levels in cells. We developed a potent and specific pan-PIM inhibitor, LGB321, which is active on PIM2 in the cellular context.LGB321 is active on PIM2-dependent multiple myeloma cell lines, where it inhibits proliferation, mTOR-C1 signaling and phosphorylation of BAD. Broad cancer cell line profiling of LGB321 demonstrates limited activity in cell lines derived from solid tumors. In contrast, significant activity in cell lines derived from diverse hematological lineages was observed, including acute lymphoblastic leukemia (ALL), acute myelogenous leukemia (AML), multiple myeloma and non-Hodgkin lymphoma (NHL). Furthermore, we demonstrate LGB321 activity in the KG-1 AML xenograft model, in which modulation of pharmacodynamics markers is predictive of efficacy. Finally, we demonstrate that LGB321 synergizes with cytarabine in this model.We have developed a potent and selective pan-PIM inhibitor with single-agent antiproliferative activity and show that it synergizes with cytarabine in an AML xenograft model. Our results strongly support the development of Pan-PIM inhibitors to treat hematologic malignancies.

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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
LGH447 LGH447 0 3
Drug Name Trade Name Synonyms Drug Classes Drug Description
LGH447 LGB321|PIM447|LGH-447|PIM-447 PIM Inhibitor (Pan) 9 LGH447 is a pan-PIM protein kinase inhibitor, which leads to cell cycle arrest and growth inhibition in PIM-expressing tumor cells (PMID: 24474669, PMID: 30370255).
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
Unknown unknown acute myeloid leukemia not applicable Cytarabine + LGH447 Preclinical Actionable In a preclinical study, the combination of LGH447 and Cytosar-U (cytarabine) resulted in tumor regression by 50% in an acute myeloid leukemia mouse model (PMID: 24474669). 24474669