title: Rational design of phosphoinositide 3-kinase α inhibitors that exhibit selectivity over the phosphoinositide 3-kinase β isoform.
abstract: Of the four class I phosphoinositide 3-kinase (PI3K) isoforms, PI3Kα has justly received the most attention for its potential in cancer therapy. Herein we report our successful approaches to achieve PI3Kα vs PI3Kβ selectivity for two chemical series. In the thienopyrimidine series of inhibitors, we propose that select ligands achieve selectivity derived from a hydrogen bonding interaction with Arg770 of PI3Kα that is not attained with the corresponding Lys777 of PI3Kβ. In the benzoxepin series of inhibitors, the selectivity observed can be rationalized by the difference in electrostatic potential between the two isoforms in a given region rather than any specific interaction.
authors: Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, United States. theffron@gene.com
authors: Timothy P
authors: TP
authors: Heffron
authors: Binqing
authors: B
authors: Wei
authors: Alan
authors: A
authors: Olivero
authors: Steven T
authors: ST
authors: Staben
authors: Vickie
authors: V
authors: Tsui
authors: Steven
authors: S
authors: Do
authors: Jennafer
authors: J
authors: Dotson
authors: Adrian J
authors: AJ
authors: Folkes
authors: Paul
authors: P
authors: Goldsmith
authors: Richard
authors: R
authors: Goldsmith
authors: Janet
authors: J
authors: Gunzner
authors: John
authors: J
authors: Lesnick
authors: Cristina
authors: C
authors: Lewis
authors: Simon
authors: S
authors: Mathieu
authors: Jim
authors: J
authors: Nonomiya
authors: Stephen
authors: S
authors: Shuttleworth
authors: Daniel P
authors: DP
authors: Sutherlin
authors: Nan Chi
authors: NC
authors: Wan
authors: Shumei
authors: S
authors: Wang
authors: Christian
authors: C
authors: Wiesmann
authors: Bing-Yan
authors: BY
authors: Zhu
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D001584:Benzoxepins / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D045744:Cell Line, Tumor; D058534:Class I Phosphatidylinositol 3-Kinases / Q000037:antagonists & inhibitors* / Q000737:chemistry; D018360:Crystallography, X-Ray; D015195:Drug Design; D004354:Drug Screening Assays, Antitumor; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology; D006801:Humans; D006860:Hydrogen Bonding; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000737:chemistry; D051379:Mice; D008958:Models, Molecular; D010879:Piperazines / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D011487:Protein Conformation; D011743:Pyrimidines / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D051381:Rats; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; D001584:Benzoxepins; D004791:Enzyme Inhibitors; D007527:Isoenzymes; D010879:Piperazines; D011743:Pyrimidines; D058534:Class I Phosphatidylinositol 3-Kinases