A Small-Molecule Inhibitor of PIM Kinases as a Potential Treatment for Urothelial Carcinomas

Abstract

The proto-oncogene proviral integration site for moloney murine leukemia virus (PIM) kinases (PIM-1, PIM-2, and PIM-3) are serine/threonine kinases that are involved in a number of signaling pathways important to cancer cells. PIM kinases act in downstream effector functions as inhibitors of apoptosis and as positive regulators of G1-S phase progression through the cell cycle. PIM kinases are upregulated in multiple cancer indications, including lymphoma, leukemia, multiple myeloma, and prostate, gastric, and head and neck cancers. Overexpression of one or more PIM family members in patient tumors frequently correlates with poor prognosis. The aim of this investigation was to evaluate PIM expression in low- and high-grade urothelial carcinoma and to assess the role PIM function in disease progression and their potential to serve as molecular targets for therapy. One hundred thirty-seven cases of urothelial carcinoma were included in this study of surgical biopsy and resection specimens. High levels of expression of all three PIM family members were observed in both noninvasive and invasive urothelial carcinomas. The second-generation PIM inhibitor, TP-3654, displays submicromolar activity in pharmacodynamic biomarker modulation, cell proliferation studies, and colony formation assays using the UM-UC-3 bladder cancer cell line. TP-3654 displays favorable human ether-à-go-go-related gene and cytochrome P450 inhibition profiles compared with the first-generation PIM inhibitor, SGI-1776, and exhibits oral bioavailability. In vivo xenograft studies using a bladder cancer cell line show that PIM kinase inhibition can reduce tumor growth, suggesting that PIM kinase inhibitors may be active in human urothelial carcinomas.

PIM kinases as therapeutic targets against advanced melanoma

“…The use of a clinically-tested PIM kinase inhibitor SGI-1776 in a melanoma mouse xenograft model in combination with a BRAF inhibitor showed that while we do not dramatically reduce total levels of PIM kinases through this method, there is therapeutic benefit in decreasing their downstream signaling effectors. For example, previous studies demonstrated that SGI-1776 causes significant tumor regressions in animal models of acute myeloid leukemia and suppresses solid tumor growth in models of bladder cancer [34, 40]. We observed that SGI-1776 also prevents melanoma tumor growth in vivo as a single agent and when combined with the BRAF inhibitor PLX4720.…”

Synthesis and Biological Evaluation of Pyrazolo[1,5-a]pyrimidine Compounds as Potent and Selective Pim-1 Inhibitors

“…18 Further, Pim-1 protein was reduced using Pim-1 shRNA compared to nontarget shRNA, and UM-UC-3 2-dimensional colony growth was markedly reduced with Pim-1 knockdown. 18 In this study, we also evaluated compound 11b's cytostatic effect on colony growth of UM-UC-3 and HSC-3 (human oral squamous carcinoma cells) cells.…”

Targeting Pim Kinases for Cancer Treatment: Opportunities and Challenges

“…Thus, SGI-9481 (also known as TP-3654) displayed submicromolar pharmacodynamic activity, and demonstrated favorable hERG and cytochrome P450 profiles compared with SGI-1776 [91,92]. SGI-9481 exhibited antitumor activity in bladder tumor xenograft model and has also been shown to inhibit a specific cell survival pathway important for acute myeloid leukemia (AML) survival, suggesting a new targeted therapeutic option for patients [93]. Other Pim kinase inhibitors in the clinical studies such as AZD1208, CX-4595, CXR1002, LGH447 (Table 1) or monoclonal antibodies have been shown to induce apoptosis affecting cell proliferation and migration, highlighting the potential for targeting Pim as an anticancer therapy [90,[94][95][96].…”

“…SGI-9481 has enhanced Pim-1 and Pim-2 inhibitory activity with K i values of 5 and 239 nM, respectively, but has a slightly reduced Pim-3 inhibition (K i = 42 nM) [91,92], compared with SGI-1776. SGI-9481 was tested against a panel of 340 kinases and displayed ten-fold or greater selectivity for Pim-1 over any other kinase tested [93]. To understand the structural basis for its activity, the crystal structure of Pim-1 in complex with an analog N-(piperidin-4-ylmethyl)-3-[3-(trif luoromethyloxy)phenyl]-[1,2,3]triazolo [4,5-b] pyridin-5-amine (PDB ID :4A7C) was used for reference protein coordinates in the creation of a model for docking of SGI-9481 as shown in Figure 5.…”