Abstract 4851: Second generation 2,3-dihydroimidazo[1,2-c]quinazoline PI3K inhibitors: development of BAY 1082439, a novel balanced PI3Ká / PI3Kâ inhibitor

The phosphoinositide-3 kinase (PI3K) pathway plays critical roles in cancer cell growth and survival, as well as in intrinsic and acquired resistance to both chemotherapy and targeted agents. These essential roles of PI3K in human cancer have led to the clinical development of PI3K pathway inhibitors. Due to the complexity derived from the existence of various PI3K isoforms (á, ß, ã, ∂), and their differential roles in signal transduction as well as cancer pathology, investigation of PI3K inhibitors with differential isoform activity profiles would allow potential use in novel indications. Mutation or amplification of PIK3CA and/or activation of PI3Ká (e.g., through oncogenic RTKs) are found frequently in a variety of cancers, making this isoform a prime target for anti-cancer therapy. In addition, the role of PI3Kß in PTEN-deficient tumors, as well as in acquired resistance to PI3Ká, has been described. This led to the hypothesis that development of a dual PI3Ká / PI3Kß inhibitor might provide a unique efficacy profile. The discovery of a novel class of 2,3-dihydroimidazo[1,2]quinazoline PI3K inhibitors, and its optimization to afford the i.v. PI3Ká/∂ inhibitor copanlisib (IC50 ratio of 1:7 in biochemical assays of PI3Ká vs. PI3Kß) has been reported recently. Herein is described the structure-activity relationship (SAR) leading to potent oral 2,3-dihydroimidazo[1,2]quinazoline PI3K inhibitors with balanced PI3Ká and PI3Kß activity, and to the selection of BAY 1082439, as a clinical candidate. BAY 1082439 has an IC50 ratio of 1:3 in biochemical assays of PI3Ká (4.9 nM) vs. PI3Kâ (15.0 nM). In addition, BAY 1082439 has unique pharmacokinetic (PK) properties with very high plasma free fractions across all species tested (33-50%), large Vss, high clearance and intermediate T1/2. Thus, BAY 1082439 represents a PI3K inhibitor with a novel pharmacological profile, warranting exploration in clinical development. BAY 1082439 is currently being studied in a phase I trial for subjects with advanced malignancies (NCT01728311). Citation Format: William J. Scott, Ningshu Liu, Andreas Hägebarth, Manfred Möwes, Ursula Mönning, Ulf Bömer, Dominik Mumberg, Franz von Nussbaum, Michael Brands, Julien Lafranc. Second generation 2,3-dihydroimidazo[1,2-c]quinazoline PI3K inhibitors: development of BAY 1082439, a novel balanced PI3Ká / PI3Kâ inhibitor. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orl