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Pan-PIM Kinase Inhibition Provides a Novel Therapy for Treating Hematological Cancers

Garcia, Pablo and Langowski, John and Wang, Yingyun and Chen, Min and Castillo, Joseph and Fanton, Christie and Zavorotinskaya, Tatiana and Dai, Yumin and Lu, Jing and Niu, Xiaohong and Basham, Stephen and Chan, Julie and Yu, Jianjun and Doyle, Michael and Feucht, Paul and Warne, Robert and Narberes, Jamie and Tsang, Tiffany and Drueckes, Peter and Trappe, Joerg and Wilson, Chris and Han, Wooseok and Lan, Jiong and Nishiguchi, Gisele and Lindvall, Mika and Bellamacina, Cornelia and Aycinena, Alex and Zang, Richard and Holash, Jocelyn and Burger, Matthew (2014) Pan-PIM Kinase Inhibition Provides a Novel Therapy for Treating Hematological Cancers. Clinical Cancer Research, 20 (7). pp. 1834-1845. ISSN 1078-0432


PIM kinases have been shown to act as oncogenes in mice, with each family member being able to drive progression of hematological cancers. Consistent with this, we found that PIMs are highly expressed in human hematological 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 hematological malignancies. However, 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. Here we describe a potent and specific Pan-PIM inhibitor, LGB321, and demonstrate that it is active on PIM2 in the cellular context of MM where it inhibits proliferation, mTOR-C1 signaling and phosphorylation of BAD. Broad cancer cell line profiling demonstrated that inhibitory activity was almost exclusively observed in cell lines from hematological lineages. Furthermore, we demonstrate LGB321 activity in human cancer cells and xenograft AML mouse models, where modulation of the pharmacodynamics markers could be used to predict efficacy. Our results strongly support the development of Pan-PIM inhibitors to treat hematological malignancies.

Item Type: Article
Date Deposited: 18 May 2016 23:45
Last Modified: 04 Jul 2016 23:46


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