title: Palomid 529, a novel small-molecule drug, is a TORC1/TORC2 inhibitor that reduces tumor growth, tumor angiogenesis, and vascular permeability.
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 show that 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.
authors.affiliation: Department of Pathology and Center for Vascular Biology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215, USA.
authors.forename: Qi
authors.initials: Q
authors.lastname: Xue
authors.forename: Benjamin
authors.initials: B
authors.lastname: Hopkins
authors.forename: Carole
authors.initials: C
authors.lastname: Perruzzi
authors.forename: Durga
authors.initials: D
authors.lastname: Udayakumar
authors.forename: David
authors.initials: D
authors.lastname: Sherris
authors.forename: Laura E
authors.initials: LE
authors.lastname: Benjamin
mesh_terms: D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001578:Benzopyrans / Q000494:pharmacology*; D002199:Capillary Permeability / Q000187:drug effects*; D002478:Cells, Cultured; D005260:Female; D006801:Humans; D051379:Mice; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation; D011494:Protein Kinases / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors; D051381:Rats; D015861:Retinal Neovascularization / Q000517:prevention & control; D058570:TOR Serine-Threonine Kinases; D015534:Trans-Activators / Q000037:antagonists & inhibitors*; D014157:Transcription Factors / Q000037:antagonists & inhibitors*; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors
chemical_list: D020533:Angiogenesis Inhibitors; D000970:Antineoplastic Agents; D001578:Benzopyrans; C500984:CRTC1 protein, human; C493245:CRTC2 protein, human; C519509:Crtc1 protein, mouse; C504923:Crtc2 protein, mouse; D000081082:Phosphoinositide-3 Kinase Inhibitors; D015534:Trans-Activators; D014157:Transcription Factors; D042461:Vascular Endothelial Growth Factor A; D011494:Protein Kinases; C546842:MTOR protein, human; C546843:mTOR protein, mouse; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; C533469:palomid 529