title: Discovery of phosphatidylinositol 3-kinase inhibitory compounds from the Screening Committee of Anticancer Drugs (SCADS) library.
abstract: Identification of new uses for existing drugs is known to be an efficient approach in drug discovery. The identification of a novel phosphatidylinositol 3-kinase (PI3K) inhibitor is important in terms of cancer chemotherapy because PI3K is implicated in many types of cancer. In an effort to discover new PI3K inhibitory compounds, we recently carried out a screening of Screening Committee of Anticancer Drugs (SCADS) library, a compound library mainly composed of antitumor drugs and kinase inhibitors. As a result, six new PI3K inhibitory compounds were identified each of which displayed over 60% inhibition of PI3Kalpha at 10 microM. Baicalein, the most potent of these inhibitors, exhibited 73% inhibition at 1 microM. Further characterization of Baicalein and Akt inhibitor VIII showed that both compounds displayed comparable inhibition against PI3Kbeta and delta, but relatively weak activity against PI3Kgamma. Growth inhibition effects of Akt inhibitor VIII and Baicalein on human cancer cell line panel JFCR39 were also investigated, and the mean logarithm of the concentration required for 50% growth inhibition of cells (Log GI50) was determined to be -5.59 and -4.70, respectively. In addition, COMPARE analysis of the two compounds together with known PI3K inhibitors was carried out by using PI3K inhibitor ZSTK474 as a seed. Our results show that Akt inhibitor VIII displays a similar fingerprint to that of ZSTK474 (r=0.633), while Baicalein does not (r=0.126). These findings suggest the inhibition profile of Baicalein in cells is different from that of a typical PI3K inhibitor.
authors.affiliation: Division of Molecular Pharmacology, Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, Tokyo, Japan.
authors.forename: Dexin
authors.initials: D
authors.lastname: Kong
authors.forename: Kanami
authors.initials: K
authors.lastname: Yamazaki
authors.forename: Takao
authors.initials: T
authors.lastname: Yamori
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D055808:Drug Discovery / Q000379:methods*; D004354:Drug Screening Assays, Antitumor / Q000379:methods*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006801:Humans; D000081082:Phosphoinositide-3 Kinase Inhibitors; D021122:Protein Subunits / Q000037:antagonists & inhibitors; D014227:Triazines / Q000737:chemistry / Q000494:pharmacology
chemical_list: D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D000081082:Phosphoinositide-3 Kinase Inhibitors; D021122:Protein Subunits; D014227:Triazines; C510150:ZSTK474