Beyond Temsirolimus: Discovery Of Pki-587 A Highly Efficacious Dual Pi3k/Mtor Inhibitor

Proceedings: AACR 101st Annual Meeting 2010‐‐ Apr 17‐21, 2010; Washington, DC Temsirolimus, a rapamycin analog, is a selective mTor inhibitor that has been successfully used in the clinic for the treatment of renal cancer. mTOR integrates signals from multiple upstream growth and survival regulatory pathways including the LKB1/AMPK and PI3K (Phosphatidylinositol-3-kinase)/Akt pathways. Among these, Phosphatidylinositol-3-kinase (PI3-K) is a lipid kinase which phophorylates phosphatidylinositol diphosphate (PIP-2) to phosphatidylinositol triphosphate. This pathway regulates cell proliferation, growth, survival, and apoptosis. The aberrant activation of PI3K-α and its downstream effectors including Akt and mTOR, has been linked to the initiation and maintenance of numerous tumor phenotypes. During tumorigenesis, PI3K/Akt/mTOR pathway activation occurs through various mechanisms, including loss of PTEN (the phosphatase that regulates PI3K signaling), over-expression or activation of certain receptor tyrosine kinases (e.g. EGFR, HER-2), interaction with activated Ras, overexpression of the PI3K-α gene (PIKC3A), or mutations in PIKC3A that cause elevated PI3K kinase activity. Deregulated PI3K/Akt/mTOR pathway signaling has been implicated in poor prognosis and low survival rate in patients with various lymphatic tumors, glioblastomas, melanomas as well as breast, prostate, lung, colon, and ovarian cancers. Numerous pre-clinical and clinical studies indicate that PI3K-α plays a key role in the biology of human cancer. Hence, it is likely that a small molecule inhibitor of both PI3K and mTOR will have clinical utility. Our project team has identified small molecules that potently inhibit the PI3K/mTor pathway. The current clinical candidate, PKI-587 (whose structure will be disclosed) is a pan PI3K (class I)/mTOR inhibitor. PKI-587 decreases tumor cell survival and proliferation in vitro. Additionally, PKI-587 has shown compelling efficacy in multiple human tumor nude mouse xenograft models such as MDA 361 (Breast), U87 (Glioma), H1975, A549 (NSCLC) in nude mice when administered as a single agent. The design of this novel potent inhibitor, synthesis, structure-activity relationships, PK and in vivo efficacy data will be presented. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 723.