RÉSUMÉ
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.
Sujet(s)
Morpholines/usage thérapeutique , Tumeurs/traitement médicamenteux , Inhibiteurs des phosphoinositide-3 kinases , Sérine-thréonine kinases TOR/antagonistes et inhibiteurs , Triazines/usage thérapeutique , Animaux , Antinéoplasiques/pharmacologie , Antinéoplasiques/usage thérapeutique , Lignée cellulaire tumorale , Femelle , Cellules HCT116 , Humains , Souris , Souris nude , Morpholines/pharmacologie , Tumeurs/métabolisme , Inhibiteurs de protéines kinases/pharmacologie , Inhibiteurs de protéines kinases/usage thérapeutique , Résultat thérapeutique , Triazines/pharmacologie , Tests d'activité antitumorale sur modèle de xénogreffeRÉSUMÉ
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.
Sujet(s)
Morpholines/composition chimique , Inhibiteurs des phosphoinositide-3 kinases , Inhibiteurs de protéines kinases/composition chimique , Sérine-thréonine kinases TOR/antagonistes et inhibiteurs , Triazines/composition chimique , Urée/analogues et dérivés , Administration par voie orale , Animaux , Lignée cellulaire tumorale , Humains , Souris , Souris nude , Morpholines/synthèse chimique , Morpholines/pharmacocinétique , Phosphatidylinositol 3-kinase/métabolisme , Inhibiteurs de protéines kinases/synthèse chimique , Inhibiteurs de protéines kinases/pharmacocinétique , Relation structure-activité , Sérine-thréonine kinases TOR/métabolisme , Triazines/synthèse chimique , Triazines/pharmacocinétique , Tropanes/composition chimique , Urée/synthèse chimique , Urée/composition chimique , Urée/pharmacocinétique , Tests d'activité antitumorale sur modèle de xénogreffeRÉSUMÉ
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.
Sujet(s)
Protéines et peptides de signalisation intracellulaire/antagonistes et inhibiteurs , Inhibiteurs des phosphoinositide-3 kinases , Inhibiteurs de protéines kinases/composition chimique , Protein-Serine-Threonine Kinases/antagonistes et inhibiteurs , Pyrimidines/composition chimique , Adénosine triphosphate/composition chimique , Adénosine triphosphate/métabolisme , Sites de fixation , Fixation compétitive , Lignée cellulaire tumorale , Simulation numérique , Humains , Protéines et peptides de signalisation intracellulaire/métabolisme , Phosphatidylinositol 3-kinases/métabolisme , Phosphorylation , Inhibiteurs de protéines kinases/synthèse chimique , Inhibiteurs de protéines kinases/pharmacologie , Protein-Serine-Threonine Kinases/métabolisme , Protéines proto-oncogènes c-akt/métabolisme , Pyrimidines/synthèse chimique , Pyrimidines/pharmacologie , Sérine-thréonine kinases TORRÉSUMÉ
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.
Sujet(s)
Inhibiteurs des phosphoinositide-3 kinases , Purines/composition chimique , Pyrazoles/composition chimique , Pyridines/composition chimique , Sites de fixation , Cellules Caco-2 , Lignée cellulaire tumorale , Cristallographie aux rayons X , Dosage immunologique par polarisation de fluorescence , Humains , Protéines et peptides de signalisation intracellulaire/métabolisme , Phosphatidylinositol 3-kinases/métabolisme , Protein-Serine-Threonine Kinases/métabolisme , Purines/synthèse chimique , Purines/pharmacologie , Pyrazoles/synthèse chimique , Pyrazoles/pharmacologie , Pyridines/synthèse chimique , Pyridines/pharmacologie , Relation structure-activité , Sérine-thréonine kinases TORRÉSUMÉ
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.