RESUMO
While the discovery of immune checkpoint inhibitors has led to robust, durable responses in a range of cancers, many patients do not respond to currently available therapeutics. Therefore, an urgent need exists to identify alternative mechanisms to augment the immune-mediated clearance of tumors. Hematopoetic progenitor kinase 1 (HPK1) is a serine-threonine kinase that acts as a negative regulator of T-cell receptor (TCR) signaling, to dampen the immune response. Herein we describe the structure-based discovery of isofuranones as inhibitors of HPK1. Optimization of the chemotype led to improvements in potency, selectivity, plasma protein binding, and metabolic stability, culminating in the identification of compound 24. Oral administration of 24, in combination with an anti-PD1 antibody, demonstrated robust enhancement of anti-PD1 efficacy in a syngeneic tumor model of colorectal cancer.
RESUMO
The design, synthesis and structure-activity relationships associated with a series of C2-substituted pyrazolopyrimidines as potent allosteric inhibitors of HIV-1 integrase (ALLINIs) are described. Structural modifications to these molecules were made in order to examine the effect on potency and, for select compounds, pharmacokinetic properties. We examined a variety of C2-substituted pyrazolopyrimidines and found that the C2-amide derivatives demonstrated the most potent antiviral activity of this class against HIV-1 infection in cell culture.
Assuntos
Amidas/farmacologia , Fármacos Anti-HIV/farmacologia , Inibidores de Integrase de HIV/farmacologia , Integrase de HIV/metabolismo , Pirazóis/farmacologia , Pirimidinas/farmacologia , Regulação Alostérica/efeitos dos fármacos , Amidas/síntese química , Amidas/química , Fármacos Anti-HIV/síntese química , Fármacos Anti-HIV/química , Células Cultivadas , Relação Dose-Resposta a Droga , Desenho de Fármacos , Inibidores de Integrase de HIV/síntese química , Inibidores de Integrase de HIV/química , HIV-1/efeitos dos fármacos , HIV-1/metabolismo , Humanos , Testes de Sensibilidade Microbiana , Estrutura Molecular , Pirazóis/síntese química , Pirazóis/química , Pirimidinas/síntese química , Pirimidinas/química , Relação Estrutura-AtividadeRESUMO
A series of 5,6,7,8-tetrahydro-1,6-naphthyridine derivatives targeting the allosteric lens-epithelium-derived-growth-factor-p75 (LEDGF/p75)-binding site on HIV-1 integrase, an attractive target for antiviral chemotherapy, was prepared and screened for activity against HIV-1 infection in cell culture. Small molecules that bind within the LEDGF/p75-binding site promote aberrant multimerization of the integrase enzyme and are of significant interest as HIV-1-replication inhibitors. Structure-activity-relationship studies and rat pharmacokinetic studies of lead compounds are presented.
