ABSTRACT
We report here the synthesis and structure-activity relationship (SAR) of a novel series of mammalian target of rapamycin (mTOR) kinase inhibitors. A series of 4,6- or 1,7-disubstituted-3,4-dihydropyrazino[2,3-b]pyrazine-2(1H)-ones were optimized for in vivo efficacy. These efforts resulted in the identification of compounds with excellent mTOR kinase inhibitory potency, with exquisite kinase selectivity over the related lipid kinase PI3K. The improved PK properties of this series allowed for exploration of in vivo efficacy and ultimately the selection of CC-223 for clinical development.
Subject(s)
Antineoplastic Agents/pharmacology , Drug Discovery , Phosphoinositide-3 Kinase Inhibitors , Prostatic Neoplasms/drug therapy , Protein Kinase Inhibitors/pharmacology , Pyrazines/pharmacology , Signal Transduction/drug effects , TOR Serine-Threonine Kinases/antagonists & inhibitors , Animals , Antineoplastic Agents/chemical synthesis , Humans , Male , Models, Molecular , Molecular Structure , Protein Kinase Inhibitors/chemical synthesis , Pyrazines/chemical synthesis , Rats , Structure-Activity Relationship , Tumor Cells, CulturedABSTRACT
We report here the synthesis and structure-activity relationship (SAR) of a novel series of triazole containing mammalian target of rapamycin (mTOR) kinase inhibitors. SAR studies examining the potency, selectivity, and PK parameters for a series of triazole containing 4,6- or 1,7-disubstituted-3,4-dihydropyrazino[2,3-b]pyrazine-2(1H)-ones resulted in the identification of triazole containing mTOR kinase inhibitors with improved PK properties. Potent compounds from this series were found to block both mTORC1(pS6) and mTORC2(pAktS473) signaling in PC-3 cancer cells, in vitro and in vivo. When assessed in efficacy models, analogs exhibited dose-dependent efficacy in tumor xenograft models. This work resulted in the selection of CC-115 for clinical development.
Subject(s)
Drug Design , Protein Kinase Inhibitors/chemistry , Protein Kinase Inhibitors/pharmacology , Pyrazines/chemistry , Pyrazines/pharmacology , TOR Serine-Threonine Kinases/antagonists & inhibitors , Triazoles/chemistry , Triazoles/pharmacology , Animals , Cell Line, Tumor , Cell Proliferation/drug effects , Dose-Response Relationship, Drug , Humans , Molecular Docking Simulation , Protein Conformation , Protein Kinase Inhibitors/metabolism , Protein Kinase Inhibitors/pharmacokinetics , Pyrazines/metabolism , Pyrazines/pharmacokinetics , Rats , Signal Transduction/drug effects , Structure-Activity Relationship , TOR Serine-Threonine Kinases/chemistry , TOR Serine-Threonine Kinases/metabolism , Triazoles/metabolism , Triazoles/pharmacokinetics , Xenograft Model Antitumor AssaysABSTRACT
We report here the discovery of a novel series of selective mTOR kinase inhibitors and the identification of CC214-2, a compound with demonstrated anti-tumor activity upon oral dosing in a PC3 prostate cancer xenograft model. A series of 4,6-disubstituted-3,4-dihydropyrazino[2,3-b]pyrazine-2(1H)-ones were discovered through a core modification of our original compound series. Analogs from this series have excellent mTOR potency and maintain selectivity over the related PI3Kα lipid kinase. Compounds such as CC214-2 were found to block both mTORC1(pS6) and mTORC2(pAktS473) signaling in PC3 cancer cells, in vitro and in vivo.
Subject(s)
Antineoplastic Agents/chemistry , Protein Kinase Inhibitors/chemistry , Pyrazines/chemistry , TOR Serine-Threonine Kinases/antagonists & inhibitors , Administration, Oral , Animals , Antineoplastic Agents/pharmacokinetics , Antineoplastic Agents/therapeutic use , Cell Line, Tumor , Cell Proliferation/drug effects , Drug Evaluation, Preclinical , Half-Life , Humans , Male , Mice , Phosphatidylinositol 3-Kinases/metabolism , Phosphoinositide-3 Kinase Inhibitors , Prostatic Neoplasms/drug therapy , Prostatic Neoplasms/metabolism , Prostatic Neoplasms/pathology , Protein Kinase Inhibitors/pharmacokinetics , Protein Kinase Inhibitors/therapeutic use , Proto-Oncogene Proteins c-akt/metabolism , Pyrazines/pharmacokinetics , Pyrazines/therapeutic use , Pyrazines/toxicity , Signal Transduction/drug effects , TOR Serine-Threonine Kinases/metabolism , Transplantation, HeterologousABSTRACT
The serine/threonine specific protein kinase B-Raf is part of the MAPK pathway and is an interesting oncology target. We have identified thieno[2,3-d]pyrimidines as a core scaffold of small molecule B-Raf inhibitors. The SAR of analogs in this series will be described.
Subject(s)
Chemistry, Pharmaceutical/methods , Protein Kinase Inhibitors/chemical synthesis , Proto-Oncogene Proteins B-raf/antagonists & inhibitors , Proto-Oncogene Proteins B-raf/metabolism , Pyrimidines/pharmacology , Crystallography, X-Ray/methods , Cyclic Nucleotide Phosphodiesterases, Type 4/chemistry , Drug Design , Humans , Inhibitory Concentration 50 , MAP Kinase Signaling System , Models, Chemical , Protein Isoforms , Protein Kinase Inhibitors/pharmacology , Structure-Activity Relationship , Urea/chemistryABSTRACT
We report here the discovery of a novel series of selective mTOR kinase inhibitors. A series of imidazo[4,5-b]pyrazin-2-ones, represented by screening hit 1, was developed into lead compounds with excellent mTOR potency and exquisite kinase selectivity. Potent compounds from this series show >1000-fold selectivity over the related PI3Kα lipid kinase. Further, compounds such as 2 achieve mTOR pathway inhibition, blocking both mTORC1 and mTORC2 signaling, in PC3 cancer cells as measured by inhibition of pS6 and pAkt (S473).
Subject(s)
Protein Kinase Inhibitors/chemistry , Protein Kinase Inhibitors/pharmacology , Pyrazines/chemistry , Pyrazines/pharmacology , TOR Serine-Threonine Kinases/antagonists & inhibitors , TOR Serine-Threonine Kinases/metabolism , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Cell Line, Tumor , Drug Discovery , Humans , Models, Molecular , Neoplasms/drug therapy , Neoplasms/enzymology , Phosphatidylinositol 3-Kinases/metabolism , Proto-Oncogene Proteins c-akt/metabolism , Signal Transduction/drug effects , Structure-Activity RelationshipABSTRACT
Starting from a phenol screening hit (6), three series of benzopyranone selective estrogen receptor modulators (SERMs) have been designed, synthesized, and analyzed for both estrogen receptor alpha binding affinity and in vitro activity in two cell assays. The lead compound identified, SP500263 (13), was more potent than raloxifene and tamoxifen in a cell-based assay measuring inhibition of interleukin-6 release.
Subject(s)
Coumarins/pharmacology , Estrogen Receptor Modulators/chemical synthesis , Estrogen Receptor alpha/metabolism , Interleukin-6/metabolism , Piperidines/pharmacology , Animals , Binding Sites , Coumarins/chemical synthesis , Estradiol/chemistry , Estradiol/pharmacology , Estrogen Antagonists/pharmacology , Estrogen Receptor Modulators/pharmacology , Female , Interleukin-6/antagonists & inhibitors , Molecular Structure , Piperidines/chemical synthesis , Raloxifene Hydrochloride/chemistry , Raloxifene Hydrochloride/pharmacology , Tamoxifen/chemistry , Tamoxifen/pharmacology , Tumor Cells, CulturedABSTRACT
Several analogues of ethyl 2-[(3-methyl-2,5-dioxo(3-pyrrolinyl))amino]-4-(trifluoromethyl)pyrimidine-5-carboxylate (1) were synthesized and tested as inhibitors of AP-1 and NF-kappaB mediated transcriptional activation in Jurkat T cells. From our SAR work, ethyl 2-[(3-methyl-2,5-dioxo(3-pyrrolinyl))-N-methylamino]-4-(trifluoromethyl)-pyrimidine-5-carboxylate was identified as a novel and potent inhibitor.
