Design And Discovery Of Pwt33597 (Vdc-597), A Dual Inhibitor Of Pi3-Kinase Alpha And Mtor

Phosphoinositide-3-kinase (PI3K) is an important mediator of tumor cell growth, survival and proliferation. In particular, PI3K alpha is important for signaling downstream of receptor tyrosine kinases and is also frequently amplified or mutationally activated in tumors, suggesting that selective inhibitors of this isoform may have therapeutic utility in the treatment of cancer. Downstream of PI3K, the mTOR kinase also plays a critical role in cellular growth and metabolism, and inhibitors of mTOR have demonstrated clinical benefit in several tumor types. We report here the design, discovery and characterization of PWT33597 (VDC-597), a dual inhibitor of PI3K alpha and mTOR, which entered human clinical trials in 2011. Starting with the known pan-Class I PI3-kinase inhibitor ZSTK474, we identified the methanesulfonylpiperazine analogue, 2-(difluoromethyl)-1-[4-[4-(methylsulfonyl)-1-piperazinyl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-1H-benzimidazole as a promising lead compound with activity against both PI3K alpha (IC 50 = 21 nM) and PI3K delta (IC 50 = 18 nM). The addition of a methoxy group at the 4-position of the benzimidazole group led to a more selective inhibitor of PI3K alpha (IC 50 = 6 nM versus 41 nM for PI3K delta), although with reduced solubility. A search for more soluble analogues identified SN 32976 as a selective inhibitor of PI3K alpha (IC 50 = 28 nM) over both PI3K delta (IC 50 = 287 nM) and mTOR (IC 50 = 227 nM), with good aqueous solubility. SN 32976 displayed good oral bioavailability and was significantly more active than ZSTK474 against a U87 MG human tumor xenograft model in mice. A search for more metabolically stable analogues subsequently identified PWT33597, which maintained the selectivity for PI3K alpha (IC 50 = 26 nM) over PI3K delta (IC 50 = 291 nM) but now also displayed activity against mTOR in biochemical assays (IC 50 = 21 nM). PWT33597 had good pharmacokinetic properties in multiple preclinical species, was not extensively metabolized in vivo and showed little potential for interaction with cytochrome P450 enzymes. Human clinical trials of PWT33597 were completed in 2012, and it is now undergoing further studies in veterinary cancers (as VDC-597). Citation Format: Gordon W. Rewcastle, Jack U. Flanagan, Anna C. Giddens, Swarna A. Gamage, Sophia KY Tsang, Jackie D. Kendall, Bruce C. Baguley, Christina M. Buchanan, David J. Matthews, Marie O9Farrell, Stephen MF Jamieson, William A. Denny, Peter R. Shepherd. Design and discovery of PWT33597 (VDC-597), a dual inhibitor of PI3-kinase alpha and mTOR. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1644. doi:10.1158/1538-7445.AM2014-1644