There is a question:the high selective inhibitors and dual inhibitors,which are better? When rapamycin is approved in 1999, more and more PI3K inhibitors were discoveried by drug development companies. In 2007, temsirolimus,a new drug for PI3K inhibition developed by Pfizer was approved. So many drug companies pay much attention to PI3K inhibitors because they believe that the PI3K pathway is almost invariably on in cancer. Vanhaesebroeck,the head of the Centre for Cell Signalling at Barts Cancer Institute: The big hit came in 2004,with the discovery of the oncogenic mutation of PIK3CA,the gene that encodes the PI3K catalytic subunit p110. This is a simple overview of PI3K-mTOR pathway. simple overview of PI3K-mTOR pathway More detail information about PI3k signal pathway, you can go to KEGG to read more about PI3K signal transduction picture and mTOR signal transduction picture. A article select some recent Phase III and II PI3K pathway inhibitors. So I list some of them on the table. Name Company Most advanced indications Phase PI3K inhibitors BKM120 Novartis Uterine (endometrial) cancer, NSCLC II GS-1101 Gilead Sciences Chronic lymphocytic leukaemia, non-Hodgkin’s lymphoma II PX-886 Oncothyreon Brain cancer II SAR-245408 Sanofi Uterine (endometrial) cancer, breast cancer II AKT inhibitors Perifosine Keryx Biopharmaceuticals Multiple myeloma, colorectal cancer III MK-2206 Merck & Co. NSCLC, haematological cancer II VQD-002 VioQuest Pharmaceuticals Solid tumours II Dual PI3KmTOR inhibitors BEZ235 Novartis Uterine (endometrial) cancer II SAR245409 Sanofi Breast cancer II There is a question. Which is better,in high selective PI3K inhibitors and dual PI3K and mTOR inhibitors? We spent a lot of money and a lot of time to find out better inhibitors.But which is better? Someone believe that dual PI3K and mTOR inhibitors are better. They think that mTOR is the downstream of PI3K and dual inhibitors of PI3K and mTOR may have better efficacy. Others consider that high select PI3K inhibitors perform better safety than dual inhibitors of PI3K and mTOR. Recently I read an article about the discovery of antitumor activity of PF-04691502. The article, â€PF-04691502, a potent and selective oral inhibitor of PI3K and mTOR kinases with antitumor activity†, was published in Molecular Cancer Therapeutics. In this poster,I will try to conclude the basic information of PF-04691502 and the anti-cancer activity of PF-04691502. PF-04691502 is a ATP-competitive dual PI3K/mTOR inhibitor which can potently and selectively inhibit class I PI3K and mTOR kinases. Researchers take PF-04691502 as a selective inhibitor of class I PI3K and mTOR because their experiment results prove that no significant inhibitory activity was observed in more than 80 protein kinases at concentration up to 10 M including the downstream kinases of PI3K such as MEK,Akt and S6K. PF-04691502 can not inhibit class III PI3K significantly. Reference: (1) Sanchez, C. G., C. X. Ma, et al. (2011). Preclinical modeling of combined phosphatidylinositol-3-kinase inhibition with endocrine therapy for estrogen receptor-positive breast cancer. Breast Cancer Res 13(2): R21. (2) Holmes, D. (2011). PI3K pathway inhibitors approach junction. Nat Rev Drug Discov 10(8): 563-564.
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