title: Functional characterization of an isoform-selective inhibitor of PI3K-p110β as a potential anticancer agent.
abstract: Genetic approaches have shown that the p110β isoform of class Ia phosphatidylinositol-3-kinase (PI3K) is essential for the growth of PTEN-null tumors. Thus, it is desirable to develop p110β-specific inhibitors for cancer therapy. Using a panel of PI3K isoform-specific cellular assays, we screened a collection of compounds possessing activities against kinases in the PI3K superfamily and identified a potent and selective p110β inhibitor: KIN-193. We show that KIN-193 is efficacious specifically in blocking AKT signaling and tumor growth that are dependent on p110β activation or PTEN loss. Broad profiling across a panel of 422 human tumor cell lines shows that the PTEN mutation status of cancer cells strongly correlates with their response to KIN-193. Together, our data provide the first pharmacologic evidence that PTEN-deficient tumors are dependent on p110β in animals and suggest that KIN-193 can be pursued as a drug to treat tumors that are dependent on p110β while sparing other PI3K isoforms.
  
  
  CONCLUSIONS
  We report the first functional characterization of a p110β-selective inhibitor, KIN-193, that is efficacious as an antitumor agent in mice. We show that this class of inhibitor holds great promise as a pharmacologic agent that could be used to address the potential therapeutic benefit of treating p110β-dependent PTEN-deficient human tumors.
authors.affiliation: Department of Cancer Biology, Dana-Farber Cancer Institute, Harvard Medical School, Massachusetts General Hospital Cancer Center, Boston, Massachusetts 02115, USA.
authors.forename: Jing
authors.initials: J
authors.lastname: Ni
authors.forename: Qingsong
authors.initials: Q
authors.lastname: Liu
authors.forename: Shaozhen
authors.initials: S
authors.lastname: Xie
authors.forename: Coby
authors.initials: C
authors.lastname: Carlson
authors.forename: Thanh
authors.initials: T
authors.lastname: Von
authors.forename: Kurt
authors.initials: K
authors.lastname: Vogel
authors.forename: Steve
authors.initials: S
authors.lastname: Riddle
authors.forename: Cyril
authors.initials: C
authors.lastname: Benes
authors.forename: Michael
authors.initials: M
authors.lastname: Eck
authors.forename: Thomas
authors.initials: T
authors.lastname: Roberts
authors.forename: Nathanael
authors.initials: N
authors.lastname: Gray
authors.forename: Jean
authors.initials: J
authors.lastname: Zhao
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D002460:Cell Line; D045744:Cell Line, Tumor; D058543:Class Ia Phosphatidylinositol 3-Kinase / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D005260:Female; D006801:Humans; D007191:Indazoles / Q000494:pharmacology / Q000627:therapeutic use; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D051058:Oncogene Protein v-akt / Q000378:metabolism; D051059:PTEN Phosphohydrolase / Q000172:deficiency; D000081082:Phosphoinositide-3 Kinase Inhibitors; D020033:Protein Isoforms / Q000037:antagonists & inhibitors / Q000378:metabolism; D013449:Sulfonamides / Q000494:pharmacology / Q000627:therapeutic use; D047368:Tumor Burden / Q000187:drug effects
chemical_list: C532162:2-(1H-indazol-4-yl)-6-(4-methanesulfonylpiperazin-1-ylmethyl)-4-morpholin-4-ylthieno(3,2-d)pyrimidine; D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D007191:Indazoles; D000081082:Phosphoinositide-3 Kinase Inhibitors; D020033:Protein Isoforms; D013449:Sulfonamides; D058543:Class Ia Phosphatidylinositol 3-Kinase; D051058:Oncogene Protein v-akt; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human