ABSTRACT
The C-C chemokine receptor 4 (CCR4) is broadly expressed on regulatory T cells (Treg) as well as other circulating and tissue-resident T cells. Treg can be recruited to the tumor microenvironment (TME) through the C-C chemokines CCL17 and CCL22. Treg accumulation in the TME has been shown to dampen the antitumor immune response and is thought to be an important driver in tumor immune evasion. Preclinical and clinical data suggest that reducing the Treg population in the TME can potentiate the antitumor immune response of checkpoint inhibitors. We have developed small-molecule antagonists of CCR4, featuring a novel piperidinyl-azetidine motif, that inhibit the recruitment of Treg into the TME and elicit antitumor responses as a single agent or in combination with an immune checkpoint blockade. The discovery of these potent, selective, and orally bioavailable CCR4 antagonists, and their activity in in vitro and in vivo models, is described herein.
Subject(s)
Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Azetidines/chemistry , Azetidines/pharmacology , Receptors, CCR4/antagonists & inhibitors , Animals , Antineoplastic Agents/pharmacokinetics , Antineoplastic Agents/therapeutic use , Azetidines/pharmacokinetics , Azetidines/therapeutic use , Cell Line, Tumor , Dogs , Humans , Macaca fascicularis , Neoplasms/drug therapy , Neoplasms/immunology , Piperidines/chemistry , Piperidines/pharmacokinetics , Piperidines/pharmacology , Piperidines/therapeutic use , Receptors, CCR4/immunology , T-Lymphocytes, Regulatory/drug effects , T-Lymphocytes, Regulatory/immunologyABSTRACT
A series of novel carbazole-containing amides and ureas were synthesized. A structure-activity relationship study of these compounds led to the identification of potent cryptochrome modulators. Based on the desired pharmacokinetic/pharmacodynamic parameters and the results of efficacy studies in db/db mice, compound 50 was selected for further profiling.
Subject(s)
Amides/pharmacology , Carbazoles/pharmacology , Cryptochromes/metabolism , Drug Discovery , Hypoglycemic Agents/pharmacology , Urea/pharmacology , Amides/chemical synthesis , Amides/chemistry , Animals , Carbazoles/chemistry , Diabetes Mellitus, Experimental/drug therapy , Diabetes Mellitus, Experimental/metabolism , Dose-Response Relationship, Drug , Hypoglycemic Agents/chemical synthesis , Hypoglycemic Agents/chemistry , Male , Mice , Molecular Structure , Obesity/drug therapy , Structure-Activity Relationship , Urea/analogs & derivatives , Urea/chemistryABSTRACT
A series of novel carbazole-containing sulfonamides and sulfamides were synthesized. A structure-activity relationship study of these compounds led to the identification of potent cryptochrome modulators. Based on the results of efficacy studies in diet-induced obese (DIO) mice, and the desired pharmacokinetic parameters, compound 41 was selected for further profiling.
