Abstract 373: Discovery of selective PI3Kb inhibitors for PTEN-deficient tumors and other indications

Abstract

Abstract PTEN somatic mutations occur in a large percentage of human cancers, from breast to prostate. Deletions of PTEN e.g. in prostate cancers are associated with tumor aggression and poor outcome, and up to 70 percent of prostate cancer patients have lost one copy of the PTEN gene at the time of diagnosis. Recent pharmacologic and genetic studies have identified the β isoform of PI3K to be required for growth of PTEN-deficient tumors in vivo and highly potent compounds are currently being explored in the clinic. These clinical candidates, however, are either limited by poor bioavailability or moderate selectivity against the delta isoform, thus warranting more selective compounds with better exposure. We have undertaken a comprehensive knowledge-based discovery of selective inhibitors of PI3Kβ with admissible pharmacokinetic and drug like properties. We have successfully identified a chemical series with potency ranging as low as 2.5 nM for PI3Kβ with >100 - fold selectivity for PI3Kδ. The α and γ isoform selectivity was around 1000 and 500 fold respectively. Compounds did not decrease insulin sensitivity and T cell proliferation thus mitigating the PI3Kα and PI3Kδ mediated side effects of nonselective inhibitors. In vitro biochemical potency translated into cell survival assay and pAKT target engagement in recombinant and wild type mammalian cell lines. In vivo tumor regression was observed in xenograft models of prostate cancer. The series did not show any observable hERG or CYP liabilities. The considerable potency, high selectivity and good bioavailability of this novel class of compounds not only makes them attractive for prostate cancer, but also for rare disease indications like hamartoma and other drug resistant cancers that are dependent on PTEN deletions. Citation Format: Arnab R. Chowdhury, Jeyaraj D. Athisayamani, Sayan Mitra, Srinivas Maddi, Ram Sudheer Adluri, Sridhar R. Bethi, Hemant Joshi, Vijaya G. Tirunagaru, Jang B. Gupta. Discovery of selective PI3Kb inhibitors for PTEN-deficient tumors and other indications. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 373.