Palomid 529, a novel small-molecule drug, is a TORC1/TORC2 inhibitor that reduces tumor growth, tumor angiogenesis, and vascular permeability

Qi Xue, Benjamin Hopkins, Carole Perruzzi, Durga Udayakumar, David Sherris, Laura E. Benjamin

Research output: Contribution to journalArticle

80 Scopus citations

Abstract

It has become clear that the phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) pathway is central for promoting both tumor and tumor stroma and is therefore a major target for anticancer drug development. First- and second-generation rapalogs (prototypical mTOR inhibitors) have shown promise but, due to the complex nature of mTOR signaling, can result in counterproductive feedback signaling to potentiate upstream Akt signaling. We present a novel PI3K/Akt/mTOR inhibitor, Palomid 529 (P529), which inhibits the TORC1 and TORC2 complexes and shows both inhibition of Akt signaling and mTOR signaling similarly in tumor and vasculature. We showtha t P529 inhibits tumor growth, angiogenesis, and vascular permeability. It retains the beneficial aspects of tumor vascular normalization that rapamycin boasts. However, P529 has the additional benefit of blocking pAktS473 signaling consistent with blocking TORC2 in all cells and thus bypassing feedback loops that lead to increased Akt signaling in some tumor cells.

Original languageEnglish (US)
Pages (from-to)9551-9557
Number of pages7
JournalCancer Research
Volume68
Issue number22
DOIs
Publication statusPublished - Nov 15 2008

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ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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