ABSTRACT
The PI3K/Akt signaling pathway is a key pathway in cell proliferation, growth, survival, protein synthesis, and glucose metabolism. It has been recognized recently that inhibiting this pathway might provide a viable therapy for cancer. A series of bis(morpholino-1,3,5-triazine) derivatives were prepared and optimized to provide the highly efficacious PI3K/mTOR inhibitor 1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]urea 26 (PKI-587). Compound 26 has shown excellent activity in vitro and in vivo, with antitumor efficacy in both subcutaneous and orthotopic xenograft tumor models when administered intravenously. The structure-activity relationships and the in vitro and in vivo activity of analogues in this series are described.
Subject(s)
Intracellular Signaling Peptides and Proteins/antagonists & inhibitors , Phosphoinositide-3 Kinase Inhibitors , Protein Kinase Inhibitors/pharmacology , Protein Serine-Threonine Kinases/antagonists & inhibitors , Triazines/pharmacology , Adenosine Triphosphate/chemistry , Adenosine Triphosphate/pharmacology , Animals , Area Under Curve , Binding, Competitive , Cell Line, Tumor , Cell Survival/drug effects , Female , Humans , Inhibitory Concentration 50 , Intracellular Signaling Peptides and Proteins/metabolism , Mice , Mice, Nude , Models, Chemical , Models, Molecular , Molecular Structure , Morpholines/chemistry , Morpholines/pharmacokinetics , Morpholines/pharmacology , Mutation , Neoplasms/metabolism , Neoplasms/pathology , Neoplasms/prevention & control , Phosphatidylinositol 3-Kinases/genetics , Phosphatidylinositol 3-Kinases/metabolism , Protein Binding , Protein Kinase Inhibitors/chemistry , Protein Kinase Inhibitors/pharmacokinetics , Protein Serine-Threonine Kinases/metabolism , Protein Structure, Tertiary , Structure-Activity Relationship , Survival Analysis , TOR Serine-Threonine Kinases , Triazines/chemistry , Triazines/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
Hemiasterlin, a tripeptide isolated from marine sponges, induces microtubule depolymerization and mitotic arrest in cells. HTI-286, an analogue from an initial study of the hemiasterlins, is presently in clinical trials. In addition to its potent antitumor effects, 2 has the advantage of circumventing the P-glycoprotein-mediated resistance that hampers the efficacy of other antimicrotubule agents such as paclitaxel and vincristine in animal models. This paper describes an in-depth study of the structure--activity relationships of analogues of 2, their effects on microtubule polymerization, and their in vitro and in vivo anticancer activity. Regions of the molecule necessary for potent activity are identified. Groups tolerant of modification, leading to novel analogues, are reported. Potent analogues identified through in vivo studies in tumor xenograft models include one superior analogue, HTI-042.
Subject(s)
Microtubules/drug effects , Microtubules/metabolism , Oligopeptides/chemistry , Oligopeptides/pharmacology , Amines/chemistry , Animals , Cell Death/drug effects , Cell Division/drug effects , Cell Line , Cyclization , Esters/chemistry , Humans , Inhibitory Concentration 50 , Methylamines/chemical synthesis , Methylamines/chemistry , Mice , Microtubules/chemistry , Molecular Structure , Neoplasms/pathology , Oligopeptides/chemical synthesis , Oxidation-Reduction , Peptides/chemical synthesis , Peptides/chemistry , Pyruvic Acid/chemistry , Structure-Activity Relationship , Tubulin/metabolismABSTRACT
Hemiasterlin is a natural product derived from marine sponges that, like other structurally diverse peptide-like molecules, binds to the Vinca-peptide site in tubulin, disrupts normal microtubule dynamics, and, at stoichiometric amounts, depolymerizes microtubules. Total synthesis of hemiasterlin and its analogues has been accomplished, and optimal pharmacological features of the series have been explored. The biological profile of one analogue, HTI-286, was studied here. HTI-286 inhibited the polymerization of purified tubulin, disrupted microtubule organization in cells, and induced mitotic arrest, as well as apoptosis. HTI-286 was a potent inhibitor of proliferation (mean IC(50) = 2.5 +/- 2.1 nM in 18 human tumor cell lines) and had substantially less interaction with multidrug resistance protein (P-glycoprotein) than currently used antimicrotubule agents, including paclitaxel, docetaxel, vinorelbine, or vinblastine. Resistance to HTI-286 was not detected in cells overexpressing the drug transporters MRP1 or MXR. In athymic mice implanted with human tumor xenografts, HTI-286 administered i.v. in saline inhibited the growth of numerous human tumors derived from carcinoma of the skin, breast, prostate, brain, and colon. Marked tumor regression was observed when used on established tumors that were >1 gram in size. Moreover, HTI-286 inhibited the growth of human tumor xenografts (e.g., HCT-15, DLD-1, MX-1W, and KB-8-5) where paclitaxel and vincristine were ineffective because of inherent or acquired resistance associated with P-glycoprotein. Efficacy was also achieved with p.o. administration of HTI-286. These data suggest that HTI-286 has excellent preclinical properties that may translate into superior clinical activity, as well as provide a useful synthetic reagent to probe the drug contact sites of peptide-like molecules that interact with tubulin.
