Preclinical characterization of PWT33597, a dual inhibitor of PI3-kinase alpha and mTOR.

Show simple item record Matthews, DJ en O’Farrell, M en James, J en Giddens, Anna en Rewcastle, Gordon en Denny, William en
dc.coverage.spatial Orlando, Florida, United States en 2012-06-12T21:03:14Z en 2011-04-05 en
dc.identifier.citation American Association of Cancer Research 102nd Annual Meeting. 05 Apr 2011 en
dc.identifier.uri en
dc.description.abstract 4485: 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 discovery and characterization of PWT33597, a dual inhibitor of PI3K alpha and mTOR. PWT33597 inhibits PI3K alpha and mTOR in biochemical assays with IC50 values of 19 and 14 nM respectively, and is approximately 10-fold selective with respect to PI3K gamma and PI3K delta. Profiling of PWT33597 against 442 protein kinases (Ambit Kinomescan) revealed little or no cross-reactivity with either serine/threonine or tyrosine kinases, and there was little cross-reactivity with an additional panel of 64 pharmacologically relevant targets. In NCI-H460 and HCT116 tumor cells with mutationally activated PI3K alpha, PWT33597 inhibits phosphorylation of PI3K and mTOR pathway proteins with cellular IC50 values similar to its biochemical IC50 values. PWT33597 has good pharmacokinetic properties in multiple preclinical species, is not extensively metabolized in vivo and shows little potential for interaction with cytochrome P450 enzymes. Following a single oral dose in vivo, PWT33597 shows durable inhibition of PI3K and mTOR pathway signaling in xenograft tumors. High compound distribution into tumors and potent anti-tumor activity has been observed in multiple tumor xenograft models with activated PI3K/mTOR pathways. Also, administration of PWT33597 in mice is associated with transient increases in plasma insulin, consistent with an effect on PI3K/AKT signaling. A robust PK/PD relationship has been defined, which will guide interpretation of the planned phase I clinical study. IND-enabling studies with PWT33597 are currently in progress. en
dc.description.uri en
dc.relation.ispartof American Association of Cancer Research 102nd Annual Meeting en
dc.relation.ispartofseries Proceedings of the American Association of Cancer Research 2011, Vol 52 en
dc.rights Items in ResearchSpace are protected by copyright, with all rights reserved, unless otherwise indicated. Previously published items are made available in accordance with the copyright policy of the publisher. en
dc.rights.uri en
dc.title Preclinical characterization of PWT33597, a dual inhibitor of PI3-kinase alpha and mTOR. en
dc.type Conference Poster en
dc.rights.holder Copyright: The Authors en en
pubs.publication-status Published en
dc.rights.accessrights en
pubs.elements-id 266228 en Medical and Health Sciences en Medical Sciences en Auckland Cancer Research en Science en Science Research en Maurice Wilkins Centre (2010-2014) en
pubs.record-created-at-source-date 2011-12-31 en

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