ABSTRACT
A pyrrolopyridinyl thiophene carboxamide 7 was discovered as a tractable starting point for a lead optimization effort in an AKT kinase inhibition program. SAR studies aided by a co-crystal structure of 7 in AKT2 led to the identification of AKT inhibitors with subnanomolar potency. Representative compounds showed antiproliferative activity as well as inhibition of phosphorylation of the downstream target GSK3beta.
Subject(s)
Drug Discovery , Protein Kinase Inhibitors/chemical synthesis , Proto-Oncogene Proteins c-akt/antagonists & inhibitors , Pyridines/chemical synthesis , Pyridines/pharmacology , Thiophenes/chemistry , Animals , Crystallography, X-Ray , Drug Discovery/methods , Humans , Mice , Protein Kinase Inhibitors/pharmacology , Proto-Oncogene Proteins c-akt/metabolism , Thienopyridines , Thiophenes/chemical synthesis , Thiophenes/pharmacologyABSTRACT
AKT inhibitors containing an imidazopyridine aminofurazan scaffold have been optimized. We have previously disclosed identification of the AKT inhibitor GSK690693, which has been evaluated in clinical trials in cancer patients. Herein we describe recent efforts focusing on investigating a distinct region of this scaffold that have afforded compounds (30 and 32) with comparable activity profiles to that of GSK690693.
Subject(s)
Oxadiazoles/chemical synthesis , Protein Kinase Inhibitors/chemical synthesis , Proto-Oncogene Proteins c-akt/antagonists & inhibitors , Animals , Cell Line , Cell Line, Tumor , Crystallography, X-Ray , Humans , Oxadiazoles/chemistry , Oxadiazoles/pharmacology , Oxadiazoles/therapeutic use , Protein Kinase Inhibitors/pharmacology , Protein Structure, Secondary/physiology , Proto-Oncogene Proteins c-akt/metabolism , Structure-Activity RelationshipABSTRACT
Tumor cells upregulate many cell signaling pathways, with AKT being one of the key kinases to be activated in a variety of malignancies. GSK2110183 and GSK2141795 are orally bioavailable, potent inhibitors of the AKT kinases that have progressed to human clinical studies. Both compounds are selective, ATP-competitive inhibitors of AKT 1, 2 and 3. Cells treated with either compound show decreased phosphorylation of several substrates downstream of AKT. Both compounds have desirable pharmaceutical properties and daily oral dosing results in a sustained inhibition of AKT activity as well as inhibition of tumor growth in several mouse tumor models of various histologic origins. Improved kinase selectivity was associated with reduced effects on glucose homeostasis as compared to previously reported ATP-competitive AKT kinase inhibitors. In a diverse cell line proliferation screen, AKT inhibitors showed increased potency in cell lines with an activated AKT pathway (via PI3K/PTEN mutation or loss) while cell lines with activating mutations in the MAPK pathway (KRAS/BRAF) were less sensitive to AKT inhibition. Further investigation in mouse models of KRAS driven pancreatic cancer confirmed that combining the AKT inhibitor, GSK2141795 with a MEK inhibitor (GSK2110212; trametinib) resulted in an enhanced anti-tumor effect accompanied with greater reduction in phospho-S6 levels. Taken together these results support clinical evaluation of the AKT inhibitors in cancer, especially in combination with MEK inhibitor.
Subject(s)
Antineoplastic Agents/pharmacology , Diamines/pharmacology , Gene Expression Regulation, Neoplastic , Pancreatic Neoplasms/drug therapy , Protein Kinase Inhibitors/pharmacology , Pyrazoles/pharmacology , Tumor Burden/drug effects , Administration, Oral , Animals , Antineoplastic Agents/chemical synthesis , Blood Glucose/metabolism , Cell Line, Tumor , Diamines/chemical synthesis , Drug Evaluation, Preclinical , Drug Synergism , Female , Humans , MAP Kinase Kinase Kinases/antagonists & inhibitors , MAP Kinase Kinase Kinases/genetics , MAP Kinase Kinase Kinases/metabolism , Mice , Mice, SCID , PTEN Phosphohydrolase/antagonists & inhibitors , PTEN Phosphohydrolase/genetics , PTEN Phosphohydrolase/metabolism , Pancreatic Neoplasms/enzymology , Pancreatic Neoplasms/genetics , Pancreatic Neoplasms/pathology , Phosphatidylinositol 3-Kinases/genetics , Phosphatidylinositol 3-Kinases/metabolism , Phosphoinositide-3 Kinase Inhibitors , Protein Kinase Inhibitors/chemical synthesis , Proto-Oncogene Proteins c-akt/antagonists & inhibitors , Proto-Oncogene Proteins c-akt/genetics , Proto-Oncogene Proteins c-akt/metabolism , Pyrazoles/chemical synthesis , Ribosomal Protein S6 Kinases/antagonists & inhibitors , Ribosomal Protein S6 Kinases/genetics , Ribosomal Protein S6 Kinases/metabolism , Signal Transduction , Xenograft Model Antitumor AssaysABSTRACT
The first total synthesis of (+/-)-ingenol has been achieved. The key features of the synthesis include the use of a highly diastereoselective Michael reaction to fix the C-11 methyl stereochemistry and the incorporation of the dimethylcyclopropane via diastereoselective carbene addition to the Delta13,14 olefin. The intramolecular dioxenone photoaddition-fragmentation sequence leads to the establishment of the critical C-8/C-10 trans intrabridgehead stereochemistry, a central challenge in the synthesis of ingenanes. The completion of the synthesis proceeds using the C-6alpha hydroxymethyl group as the sole handle for oxidation of seven contiguous carbon centers.