ABSTRACT
Modulating the chemical composition of cereblon (CRBN) binders is a critical step in the optimization process of protein degraders that seek to hijack the function of this E3 ligase. Small structural changes can have profound impacts on the overall profile of these compounds, including depth of on-target degradation, neosubstrate degradation selectivity, as well as other drug-like properties. Herein, we report the design and synthesis of a series of novel CRBN binding moieties. These CRBN binders were evaluated for CRBN binding and degradation of common neosubstrates Aiolos and GSPT1. A selection of these binders was employed for an exploratory matrix of heterobifunctional molecules, targeting CRBN-mediated degradation of the androgen receptor.
Subject(s)
Peptide Hydrolases , Ubiquitin-Protein Ligases , Proteolysis , Peptide Hydrolases/metabolism , Ubiquitin-Protein Ligases/metabolism , UbiquitinationABSTRACT
The PKC-θ isoform of protein kinase C is selectively expressed in T lymphocytes and plays an important role in the T cell antigen receptor (TCR)-triggered activation of mature T cells, T cell proliferation, and the subsequent release of cytokines such as interleukin-2 (IL-2). Herein, we report the synthesis and structure-activity relationship (SAR) of a novel series of PKC-θ inhibitors. Through a combination of structure-guided design and exploratory SAR, suitable replacements for the basic C4 amine of the original lead (3) were identified. Property-guided design enabled the identification of appropriately substituted C2 groups to afford potent analogs with metabolic stability and permeability to support in vivo testing. With exquisite general kinase selectivity, cellular inhibition of T cell activation as assessed by IL-2 expression, a favorable safety profile, and demonstrated in vivo efficacy in models of acute and chronic T cell activation with oral dosing, CC-90005 (57) was selected for clinical development.
Subject(s)
Cyclohexanols/therapeutic use , Graft vs Host Disease/drug therapy , Immunologic Factors/therapeutic use , Protein Kinase C-theta/antagonists & inhibitors , Protein Kinase Inhibitors/therapeutic use , Pyrimidines/therapeutic use , Animals , Caco-2 Cells , Cell Proliferation/drug effects , Cyclohexanols/chemical synthesis , Cyclohexanols/metabolism , Humans , Immunologic Factors/chemical synthesis , Immunologic Factors/metabolism , Lymphocyte Activation/drug effects , Male , Mice, Inbred C57BL , Molecular Docking Simulation , Molecular Structure , Protein Binding , Protein Kinase C-delta/antagonists & inhibitors , Protein Kinase C-delta/metabolism , Protein Kinase C-theta/metabolism , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/metabolism , Pyrimidines/chemical synthesis , Pyrimidines/metabolism , Structure-Activity Relationship , T-Lymphocytes/drug effectsABSTRACT
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
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
The reagent combination of catalytic amounts of copper hydride ligated by a nonracemic SEGPHOS ligand leads in situ to an extremely reactive species capable of effecting asymmetric hydrosilylations of conjugated cyclic enones in very high ees. An unprecedented substrate-to-ligand ratio as high as 275 000:1 for this transformation has been documented. [reaction: see text]
