Design and Development of a Novel Orally-Active, PI3K-p110Beta/Delta Inhibitor with Combined Tumor Immunotherapeutic, Growth Inhibition and Anti-Metastatic Activity

The phosphatidylinositide 3-kinases (PI3Ks) have emerged as important therapeutic targets for the treatment of hematological malignancies and solid tumors. In hematological cancer therapy, the majority of clinical activity has centered on the inhibition of the class IA isoform p110δ and the class IB enzyme p110γ, whereas for solid tumor treatment the landscape has been dominated by inhibitors of all four class I PI3Ks (p110α, β, δ and γ) or dual class I/mTOR inhibitors of limited selectivity. Our research has focused on the emerging role of p110β and p110δ in both cancer types, in which overexpression, mutation and PTEN-defectiveness have been shown to be key features in disease pathogenesis and progression. We have designed and developed a uniquely selective series of small molecules that inhibit the p110β/δ isoforms, and which display extremely high specificity in the human kinome. The design of such molecules has enabled us to interrogate the function of p110δ in tumor immunotherapy and p110β in primary tumor growth and metastasis; our lead compounds show promising oral activity in syngeneic models, in which they inhibit tumor growth and metastatic spread whilst also impacting on downstream biomarker responses. Additionally, through our ability to tune selectivity over p110α and p110γ, elimination of the mechanism-related toxicities associated with those isoforms can be realized, making selective dual p110β/δ inhibition potentially more conducive to combination therapy than for pan-PI3K inhibitors. Described herein is data for our clinical development candidate, KA2237, which is an orally-active, potent and selective p110β/δ inhibitor. This molecule displays potent in vitro growth inhibition and PD responses in a spectrum of hematological tumor lines, including in MCL and PTEN-null GCB-DLBCL, and has potential to treat BTK inhibitor-resistant malignancies of the hematopoietic system. KA2237 will enter Phase I studies in hematological cancer at the end of 2015.