ABSTRACT
PURPOSE: 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. EXPERIMENTAL DESIGN: 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 (â¼1,000 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). CONCLUSION: Significant antitumor efficacy and a favorable pharmacokinetic/safety profile justified phase 1 clinical evaluation of PKI-587.
Subject(s)
Morpholines/therapeutic use , Neoplasms/drug therapy , Phosphoinositide-3 Kinase Inhibitors , TOR Serine-Threonine Kinases/antagonists & inhibitors , Triazines/therapeutic use , Animals , Antineoplastic Agents/pharmacology , Antineoplastic Agents/therapeutic use , Cell Line, Tumor , Female , HCT116 Cells , Humans , Mice , Mice, Nude , Morpholines/pharmacology , Neoplasms/metabolism , Protein Kinase Inhibitors/pharmacology , Protein Kinase Inhibitors/therapeutic use , Treatment Outcome , Triazines/pharmacology , Xenograft Model Antitumor AssaysABSTRACT
A series of mono-morpholino 1,3,5-triazine derivatives (8a-8q) bearing a 3-oxa-8-azabicyclo[3.2.1]octane were prepared and evaluated for PI3-kinase/mTOR activity. Replacement of one of the bis-morpholines in lead compound 1 (PKI-587) with 3-oxa-8-azabicyclo[3.2.1]octane and reduction of the molecular weight yielded 8m (PKI-179), an orally efficacious dual PI3-kinase/mTOR inhibitor. The in vitro activity, in vivo efficacy, and PK properties of 8m are discussed.
Subject(s)
Morpholines/chemistry , Phosphoinositide-3 Kinase Inhibitors , Protein Kinase Inhibitors/chemistry , TOR Serine-Threonine Kinases/antagonists & inhibitors , Triazines/chemistry , Urea/analogs & derivatives , Administration, Oral , Animals , Cell Line, Tumor , Humans , Mice , Mice, Nude , Morpholines/chemical synthesis , Morpholines/pharmacokinetics , Phosphatidylinositol 3-Kinase/metabolism , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/pharmacokinetics , Structure-Activity Relationship , TOR Serine-Threonine Kinases/metabolism , Triazines/chemical synthesis , Triazines/pharmacokinetics , Tropanes/chemistry , Urea/chemical synthesis , Urea/chemistry , Urea/pharmacokinetics , Xenograft Model Antitumor AssaysABSTRACT
This article describes the syntheses and SAR of a series of imidazolopyrimidine derivatives, which are evaluated as inhibitors of PI3-Kinase (PI3K) and mTOR. These compounds were found to be ATP competitive with good tumor cell growth inhibition, and suppression of pathway specific biomakers such as phosphorylation of Akt at T308.
Subject(s)
Intracellular Signaling Peptides and Proteins/antagonists & inhibitors , Phosphoinositide-3 Kinase Inhibitors , Protein Kinase Inhibitors/chemistry , Protein Serine-Threonine Kinases/antagonists & inhibitors , Pyrimidines/chemistry , Adenosine Triphosphate/chemistry , Adenosine Triphosphate/metabolism , Binding Sites , Binding, Competitive , Cell Line, Tumor , Computer Simulation , Humans , Intracellular Signaling Peptides and Proteins/metabolism , Phosphatidylinositol 3-Kinases/metabolism , Phosphorylation , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/pharmacology , Protein Serine-Threonine Kinases/metabolism , Proto-Oncogene Proteins c-akt/metabolism , Pyrimidines/chemical synthesis , Pyrimidines/pharmacology , TOR Serine-Threonine KinasesABSTRACT
Series of purine and pyrazolo[3,4-d]pyrimidine inhibitors of phosphatidylinositol-3-kinases (PI3K) have been prepared. The optimized purine inhibitors show good potency in a PI3K p110alpha (PI3K-alpha) fluorescence polarization assay with good selectivity versus PI3K p110gamma (PI3K-gamma) and the mammalian target of rapamycin (mTOR). The related pyrazolo[3,4-d]pyrimidines show potent PI3K-alpha and mTOR inhibition with good selectivity versus PI3K-gamma. Representative compounds showed activity in a cellular proliferation assay against Caco-2 colorectal, LoVo colorectal and PC3MM2 prostate adenocarcinoma cancer cells. Signaling through the PI3K pathway was confirmed via inhibition of phospho-AKT in MDA-361 cells.
Subject(s)
Phosphoinositide-3 Kinase Inhibitors , Purines/chemistry , Pyrazoles/chemistry , Pyridines/chemistry , Binding Sites , Caco-2 Cells , Cell Line, Tumor , Crystallography, X-Ray , Fluorescence Polarization Immunoassay , Humans , Intracellular Signaling Peptides and Proteins/metabolism , Phosphatidylinositol 3-Kinases/metabolism , Protein Serine-Threonine Kinases/metabolism , Purines/chemical synthesis , Purines/pharmacology , Pyrazoles/chemical synthesis , Pyrazoles/pharmacology , Pyridines/chemical synthesis , Pyridines/pharmacology , Structure-Activity Relationship , TOR Serine-Threonine KinasesABSTRACT
Novel tricyclic benzazepine derivatives were synthesized as arginine vasopressin (AVP) antagonists. Several tricyclic compounds showed potent antagonistic activity in rat AVP receptors V(1a) and V(2). Derivatives containing pyrrolo-tricyclic amines, 13i-k, 30, and 31 also showed selectivity for the V(2) receptor.
