Abstract 3639: Design and development of a novel series of orally active, selective PI3K-p110β/δ inhibitors for the treatment of solid and hematological cancers

Proceedings: AACR 106th Annual Meeting 2015; April 18-22, 2015; Philadelphia, PA The phosphatidylinositide 3-kinases (PI3Ks) have emerged as important therapeutic targets for the treatment of solid and hematological malignancies. For solid tumor therapy, the majority of clinical activity has largely centered on pan-class I (p110α, β, δ and γ) inhibitors with limited selectivity, or pan-class I/mTOR dual inhibitors, whereas targeting p110δ and p110γ has been the main focus for hematological cancer treatment in the clinic. Our research at Karus in the PI3K arena has been based upon the emerging role of p110β and p110δ in PTEN-deficient solid and hematological tumorigenesis, and in the emerging role of individual PI3K isoforms in tumor immunotherapy. We have designed and developed a uniquely-selective series of orally-active molecules that inhibit the p110β/δ isoforms, 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 PI3K-p110β/δ inhibitors for the treatment of solid and hematological cancers. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3639. doi:10.1158/1538-7445.AM2015-3639