Abstract LB-7: Design and development of a novel series of orally active, selective PI3Kp110β/δ inhibitors for the treatment of cancer

Proceedings: AACR Annual Meeting 2014; April 5-9, 2014; San Diego, CA The phosphatidylinositide 3-kinases (PI3Ks) have emerged as attractive therapeutic targets for the treatment of cancer. The majority of PI3K inhibitors currently in clinical development primarily target either all four class I enzymes (p110α, β, δ and γ) with limited selectivity, or are pan-class I/mTOR dual inhibitors. Over recent years, a switch of focus to more selective PI3K inhibitors for the treatment of specific tumor types has occurred. Of particular note, p110b has been reported to be the principal isoform in driving PTEN-deficient tumorigenesis; additionally, high levels of p110δ expression in solid tumor cells have been shown to suppress PTEN activity, generating cellular sensitivity to p110δ inhibition through PTEN activation. Moreover, PI3K pathway activation in certain PTEN-null solid tumors has been shown to be mediated by both the p110β and p110δ catalytic subunits, suggesting the potential of a dual-selective p110β/δ inhibitor in this setting. During the past 12 months, the discovery of activating mutant forms of both p110β and p110δ has been reported. The strategy outlined in this presentation centres on the design and development of a new class of orally-active small molecules that selectively inhibit p110β and p110δ, and which display high degrees of specificity over protein kinases and other lipid kinases. Moreover, a spectrum of p110β/δ selectivity has been achieved in this series, which has facilitated interrogation of preferred isoform inhibition profiles required to confer tumor growth inhibition; additionally, by tuning selectivity over the other class I isoforms, elimination of the mechanism-related toxicities associated with the pan-class I inhibitors currently in the clinic can be realized, making such agents potentially more conducive to combination therapy. In vitro and in vivo therapy data for advanced lead compounds will be disclosed. Citation Format: Stephen J. Shuttleworth. Design and development of a novel series of orally active, selective PI3Kp110β/δ inhibitors for the treatment of cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr LB-7. doi:10.1158/1538-7445.AM2014-LB-7