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Ly294002 is such an important PI3K inhibitor. Today, I would look back the classic article to review some information. The article “A specific inhibitor of phosphatidylinositol 3-kinase, 2-(4- morpholinyl)-8-phenyl-4H-1-benzopyran-4-one (LY294002)” provides much important information.The article was published on the journal of biological chemistry in 1994. I suggested that anyone interested in LY294002 or PI3K inhibitors can read this article. It’s a free article now. The article was written by Lilly Research Laboratories. Before discovering and synthetizing LY294002, researchers found a PI3K inhibitor called quercetin. It’s a natural product and bioflavinoid. Researchers found that quercetin can inhibit PI3K with IC50 of 3.8uM(1.3ug/ml). And quercetin can bind to the ATP-binding site of PI3K to inhibit the activity of PI3K. But quercetin is not strong enough to inhibit PI3K. The IC50 of quercetin is too large. Besides the large IC50 value, quercetin not only inhibit PI3K, but can inhibit other veral tyrosine and serine/threonine kinases. So research study quercetin and synthetize the analogs of quercetin. And then they got LY294002 from a list of compounds including LY292223, LY292696, LY293684, LY293646, LY297978, LY303511, LY297962, LY298619, and LY297495. Those compounds shared the general structure below with some specific groups. The R1 and R2 groups are different in those compounds. LY294002 showed better inhibition of PI3K, but it still inhibit other kinase such as casein kinase II. Then I introduced the synthetic process of LY294002. Some compounds are exacted from natural products. Some are designed. Now, the researchers who are interested in discovering new inhibitors designed their compounds from a starting point, a compound which is selected for therapeutic potential from a groups of compounds which are synthesized randomly in HTS(high throughput screening test). Some PI3K inhibitors and some HIF inhibitor I reported are all discovered in this way. If you read a large amount of articles which are published in Bioorganic & Medicinal Chemistry Letters or other similar journals, you may know how popular the way is. But there are still other ways to find new inhibitors. Some compounds are derivatives of synthetic compounds made for industrial purposes but found to have therapeutic activities as well. In 1930, Gerhard Dogmagk found that prontosil rubrum which is dye had bacteriostatic effects and such finding inspired Gertrude to design compound targeting the purine pathway. Recently I read an article about the discovery of antitumor activity of PF-04691502. The article, “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. As one of the world leading suppliers of high-performance life-science products. We have over 8,000 products which consist of inhibitors, antibodies, RNAis, proteins and peptides those which focus on signaling pathways such as GSK1363089, Perifosine, GDC-0449 & so on. Furthermore, compound libraries for high-throughput screening and high-content screening are also available.
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