title: Antitumor efficacy of PKI-587, a highly potent dual PI3K/mTOR kinase inhibitor.
abstract: OBJECTIVE
  The aim of this study was to show preclinical efficacy and clinical development potential of PKI-587, a dual phosphoinositide 3-kinase (PI3K)/mTOR inhibitor.
  
  
  METHODS
  In vitro class 1 PI3K enzyme and human tumor cell growth inhibition assays and in vivo five tumor xenograft models were used to show efficacy.
  
  
  RESULTS
  In vitro, PKI-587 potently inhibited class I PI3Ks (IC(50) vs. PI3K-α = 0.4 nmol/L), PI3K-α mutants, and mTOR. PKI-587 inhibited growth of 50 diverse human tumor cell lines at IC(50) values of less than 100 nmol/L. PKI-587 suppressed phosphorylation of PI3K/mTOR effectors (e.g., Akt), and induced apoptosis in human tumor cell lines with elevated PI3K/mTOR signaling. MDA-MB-361 [breast; HER2(+), PIK3CA mutant (E545K)] was particularly sensitive to this effect, with cleaved PARP, an apoptosis marker, induced by 30 nmol/L PKI-587 at 4 hours. In vivo, PKI-587 inhibited tumor growth in breast (MDA-MB-361, BT474), colon (HCT116), lung (H1975), and glioma (U87MG) xenograft models. In MDA-MB-361 tumors, PKI-587 (25 mg/kg, single dose i.v.) suppressed Akt phosphorylation [at threonine(T)308 and serine(S)473] for up to 36 hours, with cleaved PARP (cPARP) evident up to 18 hours. PKI-587 at 25 mg/kg (once weekly) shrank large (∼1,000 mm(3)) MDA-MB-361 tumors and suppressed tumor regrowth. Tumor regression correlated with suppression of phosphorylated Akt in the MDA-MB-361 model. PKI-587 also caused regression in other tumor models, and efficacy was enhanced when given in combination with PD0325901 (MEK 1/2 inhibitor), irinotecan (topoisomerase I inhibitor), or HKI-272 (neratinib, HER2 inhibitor).
  
  
  CONCLUSIONS
  Significant antitumor efficacy and a favorable pharmacokinetic/safety profile justified phase 1 clinical evaluation of PKI-587.
authors.affiliation: Department of Oncology, Discovery Medicinal Chemistry, and Drug Safety and Metabolism, Wyeth Research now Pfizer, Pearl River, New York 10965, USA. mallonrg@gmail.com
authors.forename: Robert
authors.initials: R
authors.lastname: Mallon
authors.forename: Larry R
authors.initials: LR
authors.lastname: Feldberg
authors.forename: Judy
authors.initials: J
authors.lastname: Lucas
authors.forename: Inder
authors.initials: I
authors.lastname: Chaudhary
authors.forename: Christoph
authors.initials: C
authors.lastname: Dehnhardt
authors.forename: Efren Delos
authors.initials: ED
authors.lastname: Santos
authors.forename: Zecheng
authors.initials: Z
authors.lastname: Chen
authors.forename: Osvaldo
authors.initials: O
authors.lastname: dos Santos
authors.forename: Semiramis
authors.initials: S
authors.lastname: Ayral-Kaloustian
authors.forename: Aranapakam
authors.initials: A
authors.lastname: Venkatesan
authors.forename: Irwin
authors.initials: I
authors.lastname: Hollander
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D045744:Cell Line, Tumor; D005260:Female; D045325:HCT116 Cells; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D009025:Morpholines / Q000494:pharmacology / Q000627:therapeutic use*; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D016896:Treatment Outcome; D014227:Triazines / Q000494:pharmacology / Q000627:therapeutic use*; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D009025:Morpholines; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors; D014227:Triazines; C549060:gedatolisib; D058570:TOR Serine-Threonine Kinases