PI3Ks are lipid kinases that control signaling pathways involved in cell proliferation, motility, cell death and cell invasion. Class I PI3K contains four isoforms, p110α, p110α, p110α and p110α which carry out non redundant signaling functions. The ≤ and ≤ isoforms are ubiquitously expressed, whereas the ≤ and ≤ isoforms are expressed primarily in lymphocytes and engaged in the regulation of immune responses. A gain of function in PI3K signaling is common to many types of human cancer, specifically mutations in PIK3CA which are found in more than 30% of various solid tumor types, including, breast, endometrium, bladder, colorectal cancers as well as lung cancers. As these mutations constitutively activate the lipid kinase activity of the protein, the cancer-specific mutants of p110α appear to be ideal therapeutic targets for anticancer drug development. p110α isoform specific low molecular weight inhibitors could be efficacious against tumors harboring p110alpha mutations and provide an improved safety profile compared to current pan-PI3K modulators. The 2-aminothiazole scaffold proved to be an excellent starting point for the development of potent PI3K inhibitors. Depending on the substitution pattern good PI3Kalpha selectivity can be achieved. Systematic modification of key residues and further optimization of the drug-like and PK properties have led to the identification of NVP-BYL719, a potent and selective PI3Kalpha inhibitor with a promising biological activity. SAR leading to the discovery of NVP-BYL719 and the structural basis for the PI3Kalpha selectivity will be discussed.

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 1922. doi:1538-7445.AM2012-1922