Abstract 3748: NVP-BYL719, a novel PI3Kalpha selective inhibitor with all the characteristics required for clinical development as an anti-cancer agent

Abstract

Abstract Most of the current oncology drug discovery and development work has shifted towards molecularly targeted therapies. A key focus has been on identifying inhibitors against components of pathways that drive tumor cell proliferation, survival, and metastasis such as the PI3K/mTOR pathway, reported to be implicated in many human cancers through various mechanisms, such as, somatic PIK3CA missense mutations that occur at high frequency. These mutations are largely point mutations predominantly clustered within three hotspots in the helical and kinase domains of p110α: E542K, E545K and H1047R, which represent about 80% of the mutations observed, and confirmed to be oncogenic gain-of-function mutations. Based on these findings cancer-specific mutants of p110α appear to be ideal targets for drug development and p110α specific inhibitors, such as NVP-BYL719, could then have potential anti-cancer activity without causing the potential side effects that could be expected from interference with other Class I PI3K isoforms or other members of the PIKK family. NVP-BYL719 is best described as a PI3Kalpha inhibitor as in biochemical assays, it inhibits p110α as well as p110α most common somatic mutations (IC50=5 nM) much more potently than p110α and ≤ and has weak or no activity against p110α, Vps34 and mTOR and is selective against a wide range of protein kinases (> 50-fold). The potency and selectivity profile of NVP-BYL719 is confirmed at the cellular level, is correlated with inhibition of various PI3K/Akt downstream signaling pathway components and is associated with anti-proliferation of breast cancer cell lines harboring PIK3CA mutations. In vivo, NVP-BYL719 shows dose and time-dependent inhibition of the PI3K/Akt pathway which correlates with compound exposure and is associated with good tolerability and significant dose-dependent anti-tumor efficacy in PIK3CA mutant tumor xenograft models in rodents. Moreover, plasma insulin levels are significantly increased while blood glucose levels remained normal at all tested doses and time points indicating on-target effects of NVP-BYL719 on the regulation of metabolism. Overall, as a PI3Kalpha inhibitor, NVP-BYL719 has good drug-like and pharmacological properties and presents all the characteristics required for its ongoing Phase I clinical development in adult patients with advanced solid malignancies whose tumors have an alteration of the PIK3CA gene. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3748. doi:1538-7445.AM2012-3748