The phosphatidylinositide 3-kinases (PI3Ks) have emerged as important therapeutic targets for the treatment of solid and hematological malignancies. In solid tumor therapy, the majority of clinical activity has centered on pan-class I (p110alpha, beta, delta and gamma) inhibitors of limited selectivity, or pan-class I/mTOR dual inhibitors, whereas targeting p110delta and p110gamma has been the main focus for hematological cancer treatment. Our research at Karus has focused on the emerging role of p110beta and p110delta in both cancer types, though increasingly in solid tumors, 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 orally-active molecules that inhibit the p110beta/delta isoforms, and which display extremely high specificity in the human kinome. The design of such molecules has enabled us to interrogate the function of p110delta in solid tumor immunotherapy and p110beta in primary tumor growth and metastasis, with our lead compounds showing promising oral activity in syngeneic models, in which they inhibit tumor growth and metastatic spread whilst also impacting on downstream biomarker levels. Additionally, through our ability to tune selectivity over p110alpha and p110gamma, elimination of the mechanism-related toxicities associated with those isoforms can be realized, making selective dual p110beta/delta inhibition, described herein for our lead compound, KA2237, potentially more conducive to combination therapy than for pan-inhibitors, including with signal transduction pathway inhibitors and other immunotherapeutics. KA2237, an orally-active, potent and selective small molecule p110beta/delta inhibitor, has completed GLP toxicology and will enter Phase I studies in 2015.
Citation Format: Stephen J. Shuttleworth. Design and development of a novel series of PI3K-p110beta/delta-selective inhibitors with combined tumor immunotherapeutic, growth inhibition, and anti-metastatic activity. [abstract]. In: Proceedings of the CRI-CIMT-EATI-AACR Inaugural International Cancer Immunotherapy Conference: Translating Science into Survival; September 16-19, 2015; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(1 Suppl):Abstract nr B008.
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