Format

Send to

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

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

Author information

1
Department of Cancer Biology, Dana-Farber Cancer Institute, Harvard Medical School, Massachusetts General Hospital Cancer Center, Boston, Massachusetts 02115, USA.

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.

PMID:
22588880
PMCID:
PMC3384541
DOI:
10.1158/2159-8290.CD-12-0003
[Indexed for MEDLINE]
Free PMC Article

Publication types, MeSH terms, Substances, Grant support

Publication types

MeSH terms

Substances

Grant support

Supplemental Content

Full text links

Icon for HighWire Icon for PubMed Central
Loading ...
Support Center