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

Abstract

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 K m 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.

Discovery and Optimization of Quinazolinone-pyrrolopyrrolones as Potent and Orally Bioavailable Pan-Pim Kinase Inhibitors

“…22,23 Therefore, the Pim-3 enzyme assay was not routinely performed. In cell-based assays, the compounds were 8 30, 22 and 78 nM, respectively. Interestingly, between the set of enantiomers 8 and 9, the (R)-6'-Me enantiomer (9) was not only more potent in both enzymatic and cell-based assays, but also had lower microsomal turnover. The [5,5]-fused bicycles, 7, 9, 10, and 11, were further profiled in rat IV/PO PK.…”

“…Among the three isoforms, Pim-2 has the lowest K m (~ 4 µM) for ATP, about 100-and 10-fold lower than those of Pim-1 and Pim-3, respectively. 9 Hence, cell active pan-Pim inhibitors have been more challenging to identify than Pim-1 or Pim-3 inhibitors. 4 Many research groups have disclosed ATP-competitive Pim kinase inhibitors of diverse chemical scaffolds with a wide range of cell potency.…”

Targeting Pim Kinases for Cancer Treatment: Opportunities and Challenges

“…The rest of the loop is then moved away from the catalytic center so that the C-terminal part provides a platform for substrate binding. [128] and highly selective against 442 kinases [129].…”

“…LGB321, a 6-phenyl-N-(pyridin-3-yl)picolinamidebased derivative ( Figure 5 & Table 1), is the most potent Pim inhibitor identified to date and has the K i values of 1.0, 2.1 and 0.8 pM for Pim-1, -2 and -3, respectively [128]. Furthermore, it is highly selective against 442 kinases [129].…”

Discovery and Optimization of Macrocyclic Quinoxaline-pyrrolo-dihydropiperidinones as Potent Pim-1/2 Kinase Inhibitors

“…It is now widely recognized that cellular inhibition of Pim-2 kinase is a significant challenge, due in part to the low K m of Pim-2 kinase for adenosine triphosphate (ATP), and very few Pim inhibitors have been reported to achieve submicromolar IC 50 values in Pim-2 overexpressing cell lines. 5 Reported herein is the discovery and optimization of a class of macrocyclic Pim-1/2 kinase inhibitors with double-digit nanomolar activity in KMS-12-BM, a multiple myeloma cell line with relatively high endogenous levels of Pim-1/2. 6 Screening of kinase inhibitors from prior kinase programs identified a naphthyridine pyrrolodihydropiperidinone as a potent Pim-1/2 kinase inhibitor that exhibited poor selectivity against many kinase off-targets ( Figure 1).…”