RESUMO
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.
Assuntos
Antineoplásicos/química , Antineoplásicos/farmacologia , Azetidinas/química , Azetidinas/farmacologia , Receptores CCR4/antagonistas & inibidores , Animais , Antineoplásicos/farmacocinética , Antineoplásicos/uso terapêutico , Azetidinas/farmacocinética , Azetidinas/uso terapêutico , Linhagem Celular Tumoral , Cães , Humanos , Macaca fascicularis , Neoplasias/tratamento farmacológico , Neoplasias/imunologia , Piperidinas/química , Piperidinas/farmacocinética , Piperidinas/farmacologia , Piperidinas/uso terapêutico , Receptores CCR4/imunologia , Linfócitos T Reguladores/efeitos dos fármacos , Linfócitos T Reguladores/imunologiaRESUMO
Recruitment of suppressive CD4+ FOXP3+ regulatory T cells (Treg) to the tumor microenvironment (TME) has the potential to weaken the antitumor response in patients receiving treatment with immuno-oncology (IO) agents. Human Treg express CCR4 and can be recruited to the TME through the CC chemokine ligands CCL17 and CCL22. In some cancers, Treg accumulation correlates with poor patient prognosis. Preclinical data suggests that preventing the recruitment of Treg and increasing the population of activated effector T cells (Teff) in the TME can potentiate antitumor immune responses. We developed a novel series of potent, orally bioavailable small molecule antagonists of CCR4. From this series, several compounds exhibited high potency in distinct functional assays in addition to good in vitro and in vivo ADME properties. The design, synthesis, and SAR of this series and confirmation of its in vivo activity are reported.
Assuntos
Movimento Celular/efeitos dos fármacos , Pirazinas/farmacologia , Pirazóis/farmacologia , Receptores CCR4/antagonistas & inibidores , Linfócitos T Reguladores/efeitos dos fármacos , Microambiente Tumoral/efeitos dos fármacos , Animais , Cicloexanos/síntese química , Cicloexanos/farmacocinética , Cicloexanos/farmacologia , Descoberta de Drogas , Humanos , Camundongos Transgênicos , Estrutura Molecular , Piperazinas/síntese química , Piperazinas/farmacocinética , Piperazinas/farmacologia , Pirazinas/síntese química , Pirazinas/farmacocinética , Pirazóis/síntese química , Pirazóis/farmacocinética , Ratos , Relação Estrutura-AtividadeRESUMO
Alstonine and serpentine are pentacyclic indoloquinolizidine alkaloids (referred to as "anhydronium bases") containing three contiguous stereocenters. Each possesses interesting biological activity, with alstonine being the major component of a plant-based remedy to treat psychosis and other nervous system disorders. This work describes the enantioselective total syntheses of these natural products with a cooperative hydrogen bonding/enamine-catalyzed Michael addition as the key step.
Assuntos
Aminas/química , Produtos Biológicos/síntese química , Ioimbina/síntese química , Produtos Biológicos/química , Catálise , Cristalografia por Raios X , Ligação de Hidrogênio , Modelos Moleculares , Estrutura Molecular , Estereoisomerismo , Ioimbina/químicaRESUMO
A convergent, catalytic asymmetric formal [4 + 2] annulation for the synthesis of dihydroquinolones has been developed. Carboxylic acids can be employed as precursors to NHC enolates through an in situ activation strategy. Simultaneous generation of a reactive aza-o-quinone methide under the basic conditions employed for NHC generation leads to a dual activation approach.
Assuntos
Alcenos/química , Azóis/química , Quinolonas/síntese química , Ácidos Carboxílicos/química , Catálise , Indolquinonas/síntese química , Indolquinonas/química , Modelos Moleculares , Quinolonas/química , EstereoisomerismoRESUMO
A reaction between imines and anhydrides has been developed with chiral disubstituted anhydrides and chiral imines. The synthesis of highly substituted γ-lactams with three stereogenic centers, including one quaternary center, proceeds at room temperature in high yield and with high diastereoselectivity in most cases. Enantiomerically pure alkyl-substituted anhydrides proceed with no epimerization, thus providing access to enantiomerically pure penta-substituted lactam products.
Assuntos
Iminas/química , Lactamas/síntese química , Anidridos Succínicos/química , Lactamas/química , Estrutura Molecular , EstereoisomerismoRESUMO
The first synthesis of heliotropamide is reported. The preparation of this 2-oxopyrrolidine (γ-lactam) natural product relied on a diastereoselective one-pot, four-component reaction (4CR) for the assembly of the core structure. On the basis of chemical shift correlation and NOESY experiments, the previously unknown alkene geometry of heliotropamide is assigned as E.
Assuntos
Lactamas/síntese química , Pirrolidinas/síntese química , Lactamas/química , Espectroscopia de Ressonância Magnética , Estrutura Molecular , Pirrolidinas/química , EstereoisomerismoRESUMO
Interest in multicomponent reactions (MCRs) has surged during the past two decades as interest in the efficient synthesis of small molecule libraries has gained prominence. MCRs fill an important niche in library synthesis by providing direct access to library compounds and by serving as starting points for Diversity-Oriented Synthesis (DOS). Recent advances in the area of MCR chemistry have included the discovery of new reactions, development of the first asymmetric catalysts, and the application of MCRs to natural products and other targets of biological interest. This review will highlight recent developments in MCRs as a rich source of molecular diversity.