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A small-molecule inhibitor of PIM kinases as a potential treatment for urothelial carcinomas

Jason M Foulks1, Kent J Carpenter2, Bai Luo1

  • 1Astex Pharmaceuticals, Inc, Salt Lake City, UT.

Neoplasia (New York, N.Y.)
|June 24, 2014
PubMed

Insights

Proviral integration site for moloney murine leukemia virus (PIM) kinases are upregulated in urothelial carcinoma, driving cancer progression. PIM kinase inhibitors show promise as novel therapeutic targets for bladder cancer treatment.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Signaling

Background:

  • Proviral integration site for moloney murine leukemia virus (PIM) kinases (PIM-1, PIM-2, PIM-3) are serine/threonine kinases crucial for cancer cell signaling.
  • PIM kinases regulate apoptosis and cell cycle progression (G1-S phase), and their overexpression correlates with poor prognosis in various cancers.
  • Urothelial carcinoma, including bladder cancer, exhibits upregulation of PIM family members, indicating their potential role in disease progression.

Purpose of the Study:

  • To evaluate PIM kinase expression in low- and high-grade urothelial carcinoma.
  • To assess the role of PIM kinases in urothelial carcinoma progression.
  • To investigate the therapeutic potential of PIM kinase inhibitors in urothelial carcinoma.

Main Methods:

  • Analysis of PIM expression in 137 urothelial carcinoma surgical specimens (biopsy and resection).
  • In vitro studies using the UM-UC-3 bladder cancer cell line to assess the efficacy of the second-generation PIM inhibitor TP-3654.
  • In vivo xenograft studies in mice using a bladder cancer cell line to evaluate the impact of PIM kinase inhibition on tumor growth.

Main Results:

  • High expression levels of all three PIM family members were detected in both noninvasive and invasive urothelial carcinomas.
  • The PIM inhibitor TP-3654 demonstrated submicromolar activity in inhibiting cell proliferation and modulating biomarkers.
  • TP-3654 exhibited favorable safety profiles (hERG, CYP450) and oral bioavailability compared to first-generation inhibitors.
  • In vivo studies showed that PIM kinase inhibition by TP-3654 reduced tumor growth in bladder cancer xenografts.

Conclusions:

  • PIM kinases are highly expressed in urothelial carcinoma and play a significant role in disease progression.
  • PIM kinase inhibition, exemplified by TP-3654, represents a promising therapeutic strategy for urothelial carcinoma.
  • Targeting PIM kinases offers a potential new avenue for treating bladder cancer and related malignancies.

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