Functional characterization of an isoform-selective inhibitor of PI3K-p110β as a potential anticancer agent

Cancer Discov. 2012 May;2(5):425-33. doi: 10.1158/2159-8290.CD-12-0003. Epub 2012 Apr 12.

Abstract

Genetic approaches have shown that the p110β isoform of class Ia phosphatidylinositol-3-kinase (PI3K) is essential for the growth of PTEN-null tumors. Thus, it is desirable to develop p110β-specific inhibitors for cancer therapy. Using a panel of PI3K isoform-specific cellular assays, we screened a collection of compounds possessing activities against kinases in the PI3K superfamily and identified a potent and selective p110β inhibitor: KIN-193. We show that KIN-193 is efficacious specifically in blocking AKT signaling and tumor growth that are dependent on p110β activation or PTEN loss. Broad profiling across a panel of 422 human tumor cell lines shows that the PTEN mutation status of cancer cells strongly correlates with their response to KIN-193. Together, our data provide the first pharmacologic evidence that PTEN-deficient tumors are dependent on p110β in animals and suggest that KIN-193 can be pursued as a drug to treat tumors that are dependent on p110β while sparing other PI3K isoforms.

Significance: We report the first functional characterization of a p110β-selective inhibitor, KIN-193, that is efficacious as an antitumor agent in mice. We show that this class of inhibitor holds great promise as a pharmacologic agent that could be used to address the potential therapeutic benefit of treating p110β-dependent PTEN-deficient human tumors.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents / pharmacology
  • Antineoplastic Agents / therapeutic use*
  • Cell Line
  • Cell Line, Tumor
  • Class Ia Phosphatidylinositol 3-Kinase / metabolism
  • Enzyme Inhibitors / pharmacology
  • Enzyme Inhibitors / therapeutic use*
  • Female
  • Humans
  • Indazoles / pharmacology
  • Indazoles / therapeutic use
  • Male
  • Mice
  • Mice, Nude
  • Neoplasm Transplantation
  • Neoplasms / drug therapy*
  • Neoplasms / metabolism
  • Neoplasms / pathology
  • Oncogene Protein v-akt / metabolism
  • PTEN Phosphohydrolase / deficiency
  • Phosphoinositide-3 Kinase Inhibitors*
  • Protein Isoforms / antagonists & inhibitors
  • Protein Isoforms / metabolism
  • Sulfonamides / pharmacology
  • Sulfonamides / therapeutic use
  • Tumor Burden / drug effects

Substances

  • 2-(1H-indazol-4-yl)-6-(4-methanesulfonylpiperazin-1-ylmethyl)-4-morpholin-4-ylthieno(3,2-d)pyrimidine
  • Antineoplastic Agents
  • Enzyme Inhibitors
  • Indazoles
  • Phosphoinositide-3 Kinase Inhibitors
  • Protein Isoforms
  • Sulfonamides
  • Class Ia Phosphatidylinositol 3-Kinase
  • Oncogene Protein v-akt
  • PTEN Phosphohydrolase
  • PTEN protein, human