title: Studies on the mechanism of phosphatidylinositol 3-kinase inhibition by wortmannin and related analogs.
abstract: Wortmannin, a fungal metabolite, was identified as a potent inhibitor (IC50 = 4.2 nM) of phosphatidylinositol 3-kinase (PI 3-kinase). Due to the importance of PI 3-kinase in several intracellular signaling pathways, structure-activities studies on wortmannin analogs were performed in an effort to understand the structural requirements necessary for PI 3-kinase inhibition. Since wortmannin is an irreversible inhibitor of PI 3-kinase, it was postulated that covalent attachment at the electrophilic C-21 site was a possible mode of action for PI 3-kinase inhibition. We have prepared various wortmannin analogs which address the possibility of this mechanism. Of particular interest are compounds which affect the C-21 position of wortaminnin either sterically or electronically. Our results support the conclusion that nucleophilic addition by the kinase onto the C-21 position of wortmannin is required for inhibition of PI 3-kinase by wortmannin analogs. Additionally, we have prepared several D-ring analogs of wortmannin, and their activities are reported herein. We conclude that the wortmannin D ring is an important recognition site since modifications have such a dramatic effect on inhibitor potency. Finally, the identification of 17beta-hydroxywortmannin represents the first reported subnanomolar inhibitor of PI 3-kinase. These studies, along with in vivo antitumor experiments, suggest that the mechanism of PI 3-kinase inhibition correlates to the associated toxicity observed with wortmannin-based inhibitors of PI 3-kinase.
authors.affiliation: Eli Lilly and Company, Lilly Research Laboratories, Lilly Corporate Center, Indianapolis, Indiana 46285, USA.
authors.forename: B H
authors.initials: BH
authors.lastname: Norman
authors.forename: C
authors.initials: C
authors.lastname: Shih
authors.forename: J E
authors.initials: JE
authors.lastname: Toth
authors.forename: J E
authors.initials: JE
authors.lastname: Ray
authors.forename: J A
authors.initials: JA
authors.lastname: Dodge
authors.forename: D W
authors.initials: DW
authors.lastname: Johnson
authors.forename: P G
authors.initials: PG
authors.lastname: Rutherford
authors.forename: R M
authors.initials: RM
authors.lastname: Schultz
authors.forename: J F
authors.initials: JF
authors.lastname: Worzalla
authors.forename: C J
authors.initials: CJ
authors.lastname: Vlahos
mesh_terms: D000730:Androstadienes / Q000737:chemistry* / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D018360:Crystallography, X-Ray; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D008325:Mammary Neoplasms, Experimental / Q000188:drug therapy; D051379:Mice; D008958:Models, Molecular; D008968:Molecular Conformation; D015394:Molecular Structure; D009368:Neoplasm Transplantation; D019869:Phosphatidylinositol 3-Kinases; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship; D013816:Thermodynamics; D014407:Tumor Cells, Cultured; D000077191:Wortmannin
chemical_list: D000730:Androstadienes; D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D019869:Phosphatidylinositol 3-Kinases; D017853:Phosphotransferases (Alcohol Group Acceptor); D000077191:Wortmannin