RESUMO
HDAC8 is a therapeutic target with great promise for breast cancer. Here, we reported a novel compound corallorazine D from Nocardiopsis sp. XZB108, selectively inhibited HDAC8 (IC50 = 0.90 ± 0.014 µM), suggesting that it may be a promising nonhydroxamate HDAC8 inhibitor. Upon additional modifications of corallorazine D, a candidate compound 5k, demonstrated remarkable inhibitory potency against HDAC8 (IC50 = 0.12 ± 0.01 nM), 89-fold superior to PCI-34051. The selectivity of 5k was at least 439-fold, superior to corallorazine D, confirming the efficacy of our modifications. In an orthotopic mouse model of breast cancer, 5k displayed nearly 4-fold superior antitumor activity than SAHA. Furthermore, 5k triggered antitumor immunity by activating T cells. Treatment with 5k significantly increased the proportion of M1 macrophages and decreased the proportion of M2 macrophages (M1/M2 ratio = 2.67 ± 0.25). 5k represents a promising compound for further investigation as a potential treatment for breast cancer.
Assuntos
Antineoplásicos , Neoplasias da Mama , Inibidores de Histona Desacetilases , Histona Desacetilases , Animais , Feminino , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Humanos , Inibidores de Histona Desacetilases/farmacologia , Inibidores de Histona Desacetilases/síntese química , Inibidores de Histona Desacetilases/química , Inibidores de Histona Desacetilases/uso terapêutico , Camundongos , Antineoplásicos/farmacologia , Antineoplásicos/química , Antineoplásicos/síntese química , Antineoplásicos/uso terapêutico , Histona Desacetilases/metabolismo , Linhagem Celular Tumoral , Proteínas Repressoras/antagonistas & inibidores , Proteínas Repressoras/metabolismo , Relação Estrutura-Atividade , Camundongos Endogâmicos BALB C , Proliferação de Células/efeitos dos fármacos , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Psoriasis, a prevalent chronic skin disorder, remains a significant therapeutic obstacle. This study centers on rho-associated coiled-coil-containing kinase2 (ROCK2) as an advantageous target for treating psoriasis and identifies five potent and selective ROCK2 inhibitors (A31-35). Notably, A32-35 outperform KD025 in ROCK2/ROCK1 selectivity by up to 216-fold. Among these candidates, A31 emerged as an exceedingly promising molecule, showcasing remarkable inhibitory potency (IC50 = 3.7 ± 0.8 nM), 19-fold ROCK2/ROCK1 selectivity, and favorable pharmacokinetics. Insights from the binding mode study further underscored the pivotal role of interactions with Phe103 on the P-loop in determining the selectivity between ROCK1 and ROCK2. In an imiquimod-induced psoriasis-like mouse model, oral administration of A31 notably ameliorated symptoms by targeting the IL-23/Th17 axis. Based on these compelling findings, A31 was selected as a highly promising compound for further investigation as a potential treatment for psoriasis.
Assuntos
Psoríase , Animais , Camundongos , Psoríase/induzido quimicamente , Psoríase/tratamento farmacológico , Quinases Associadas a rhoRESUMO
Alpiniamides E-G, three previously unreported linear polyketide derivatives, along with two known compounds, were isolated from Streptomyces sp. QHA48, which was isolated from the saline lakes of Qinghai-Tibet Plateau. The structures of these compounds were determined through analysis of their spectroscopic data, as well as density functional theory prediction of NMR chemical shifts, application of the DP4+ algorithm and electronic circular dichroism (ECD) calculations. In a cell-based lipid-lowering assay, all five alpiniamides exhibited significant inhibition of lipid accumulation in HepG2 cells without inducing cytotoxic effects at a concentration of 27â µM.