ABSTRACT
Many patients with multiple myeloma (MM) initially respond to treatment with modern combination regimens including immunomodulatory agents (lenalidomide and pomalidomide) and proteasome inhibitors. However, some patients lack an initial response to therapy (i.e., are refractory), and although the mean survival of MM patients has more than doubled in recent years, most patients will eventually relapse. To address this need, we explored the potential of novel cereblon E3 ligase modulators (CELMoDs) for the treatment of patients with relapsed or refractory multiple myeloma (RRMM). We found that optimization beyond potency of degradation, including degradation efficiency and kinetics, could provide efficacy in a lenalidomide-resistant setting. Guided by both phenotypic and protein degradation data, we describe a series of CELMoDs for the treatment of RRMM, culminating in the discovery of CC-92480, a novel protein degrader and the first CELMoD to enter clinical development that was specifically designed for efficient and rapid protein degradation kinetics.
Subject(s)
Adaptor Proteins, Signal Transducing/metabolism , Antineoplastic Agents/pharmacology , Multiple Myeloma/drug therapy , Ubiquitin-Protein Ligases/metabolism , Adaptor Proteins, Signal Transducing/antagonists & inhibitors , Animals , Antineoplastic Agents/chemistry , Antineoplastic Agents/therapeutic use , Cell Line, Tumor , Cell Proliferation/drug effects , Female , Humans , Inhibitory Concentration 50 , Mice , Multiple Myeloma/pathology , Recurrence , Stereoisomerism , Treatment Failure , Ubiquitin-Protein Ligases/antagonists & inhibitors , Xenograft Model Antitumor AssaysABSTRACT
Due to their diverse range of biological activities, imidazoheterocycles are recognized as privileged structures making these structural motifs attractive targets for library preparation. We report herein the synthesis of a sizable collection of imidazo[1,2- a]heterocycle scaffolds well-suited for divergent library preparation by virtue of amine functional handles with diverse positioning and connectivities. Partial reduction of imidazo[1,2- a]pyrazines to the tetrahydroimidazo[1,2- a]pyrazines and regiospecific Mannich-type bond formation at the C-3 of imidazo[1,2- a]pyridine under mild conditions achieved additional topological and connective diversity within the scaffold collection. Subsequent parallel reaction of the functionalized imidazoheterocycles with polystyrene-tetrafluorophenol esters and sulfonates produced a 7500 compound library in high purity.
Subject(s)
Aldehydes/chemistry , Amines/chemistry , Combinatorial Chemistry Techniques , Heterocyclic Compounds/chemical synthesis , Imidazoles/chemical synthesis , Nitriles/chemistry , Chemistry, Pharmaceutical , Chromatography, High Pressure Liquid , Esters/chemistry , Models, Chemical , Phenols/chemistry , Polystyrenes/chemistry , Pyridines/chemistry , Sulfonic Acids/chemistryABSTRACT
[reaction: see text] Glyoxylic acid, either in solution or immobilized on MP-carbonate (MP-glyoxylate), participates in an uncatalyzed 3-CC with 2-aminoazines and isonitriles to afford novel 2-unsubstituted-3-amino-imidazoheterocycles. MP-glyoxylate serves as a particularly efficient and experimentally convenient formaldehyde equivalent and readily liberates products through decarboxylation/self-release from the resin. These examples furthermore constitute the first application in which MP-CO3 serves as a solid support for transformations involving carboxylic acids.
Subject(s)
Aldehydes/chemistry , Azoles/chemistry , Glyoxylates/chemistry , Imidazoles/chemical synthesis , Nitriles/chemistry , Cyclization , Imidazoles/chemistry , Molecular StructureABSTRACT
[reaction: see text] The bicyclocondensation of 3-aza-1,5-ketoacids and amino alcohols furnished novel oxazolo[3,2-a]pyrazin-5-one scaffolds possessing angular, ring junction substituents in high yield with excellent levels of substrate-based diastereocontrol. Mild oxidation of serinol-derived scaffolds provided access to a new class of constrained dipeptide surrogates. Deprotection of the endocyclic amine contained within these scaffolds allows for further diversification via N-functionalization.