American Association for Cancer Research
10780432ccr132062-sup-ccr-13-2062figs1-5tabs1-2.pdf (341.76 kB)

Supplementary Figures 1 - 5, Tables 1 - 2 from Pan-PIM Kinase Inhibition Provides a Novel Therapy for Treating Hematologic Cancers

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journal contribution
posted on 2023-03-31, 17:51 authored by Pablo D. Garcia, John L. Langowski, Yingyun Wang, Min Chen, Joseph Castillo, Christie Fanton, Marjorie Ison, Tatiana Zavorotinskaya, Yumin Dai, Jing Lu, Xiao-Hong Niu, Stephen Basham, Julie Chan, Jianjun Yu, Michael Doyle, Paul Feucht, Robert Warne, Jamie Narberes, Tiffany Tsang, Christine Fritsch, Audrey Kauffmann, Estelle Pfister, Peter Drueckes, Joerg Trappe, Christopher Wilson, Wooseok Han, Jiong Lan, Gisele Nishiguchi, Mika Lindvall, Cornelia Bellamacina, J. Alex Aycinena, Richard Zang, Jocelyn Holash, Matthew T. Burger

PDF file - 346KB, Supplementary Figure 1. Normal vs. Tumor expression of PIM kinases mRNA across 17 tissue types. Supplementary Figure 2. Comparison of LGB321 on-target activity vs. Previously described pan-PIM inhibitor. Supplementary Figure 3. KINOMESCANTM of 1 mu M LGB321. Supplementary Figure 4. Biochemical and cellular selectivity of the LGB321 PIM inhibitor series towards GSK3 beta. Supplementary Figure 5. LGB321 does not inhibit EGFR signaling in HCC1954 cells. Supplementary Table 1. Sensitivity to LGB321 and Erlotinib of Lung Cells in the CCLE. Supplementary Table 2. Sensitivity to LGB321 of hematological malignacies cell lines.



Purpose: 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.Experimental Design: 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.Results: 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.Conclusions: 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. Clin Cancer Res; 20(7); 1834–45. ©2014 AACR.

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