Abstract 4501: INK1117: A potent and orally efficacious PI3Kα-selective inhibitor for the treatment of cancer
Authors: Jessen Katayoun A. , Kessler Linda , Kucharski Jeff , Guo Xin , Staunton Jocelyn , Elia Marikka , Janes Matthew , Lan Lucy , Wang Shunyou , Stewart Josh , Darjania Levan , Li Liansheng , Chan Katrina , Martin Michael , Ren Pingda , Fruman David , Rommel Christian , Liu Yi 
Published: June 2012

Objective: Discovery, characterization and preclinical evaluation of PI3Kalpha (PI3Kα) selective small molecule kinase inhibitors for the treatment of solid tumors.

Background: The PI3K pathway is one of the most frequently dysregulated pathways in human cancer. Activating mutations in the PIK3CA gene, encoding the p110 catalytic subunit of PI3Kα, have been identified as a major mechanism of inducing oncogenic PI3K signaling. The high frequency of PIK3CA mutations suggests that PI3Kα inhibitors may have therapeutic utility in genetically defined tumor populations. The discovery of isoform-selective PI3Kα inhibitors has proven to be difficult due to the highly homologous nature of all PI3K isoforms and structurally related kinases. Multiple non-selective class I PI3K (pan-PI3K) inhibitors have entered clinical development. PI3Kα-selective inhibitors may permit more potent inhibition of PI3Kα while minimizing side effects and permitting more alternatives for combination therapy relative to pan-PI3K pathway inhibitors.

Results: Through structure-guided drug design we have discovered INK1117, a novel, potent and selective PI3Kα inhibitor with good oral bioavailability. INK1117 potently inhibits PI3Kα and demonstrates a greater than 100-fold selectivity relative to other class I PI3K family members and mTOR as well as a high degree of selectivity against a large panel of protein kinases. INK1117 blocks proliferation of tumor cell lines bearing PIK3CA mutations, and inhibits cellular phosphorylation and activity of AKT. However, INK1117 shows much less activity in PTEN-deficient tumor cells, which typically display constitutive PI3K pathway activation independent of PI3Kα. INK1117 blocks VEGF signaling and angiogenesis in vitro and in vivo. Daily, oral administration of INK1117 potently inhibits tumor growth in xenograft models bearing PIK3CA oncogenic mutations and, comparable to in vitro studies, INK1117 was not efficacious in tumor models with PTEN and/or KRAS mutations. In contrast to pan-PI3K inhibitors, INK1117 does not appear to impair glucose homeostasis or insulin response in glucose/insulin tolerance tests in rodents. Additionally, INK1117 does not significantly impair B and T cell function in vitro and in vivo. These two factors support the hypothesis that INK1117 may be better tolerated than pan-PI3K inhibitors, particularly when used in combination with other agents.

Conclusion: INK1117 is a potent and orally efficacious PI3Kα isoform-selective kinase inhibitor with excellent drug-like properties. Selectively targeting PI3Kα offers a new therapeutic approach for the treatment of cancers with PIK3CA activation and preclinical data suggest that isoform-selective inhibitors may provide equivalent efficacy to pan-PI3K inhibitors in selected tumors with a more favorable safety profile.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4501. doi:10.1158/1538-7445.AM2011-4501