RESUMEN
Targeting the programmed cell death-1/ligand 1 (PD-1/PD-L1) pathway is one of the most promising cancer treatment strategies. Studies have shown that HDAC inhibitors can enhance the antitumor immune response by modulating the expression of PD-L1. Herein, we designed and synthesized a series of novel hydrazide-based small molecule HDAC inhibitors; among them, compound HQ-30 showed selective HDAC3 inhibition (IC50 = 89 nM) and remarkable PD-L1-degrading activity (DC50 = 5.7 µM, Dmax = 80% at 10 µM). Further studies revealed that HQ-30 induced the degradation of PD-L1 by regulating cathepsin B (CTSB) in the lysosomes. Further, HQ-30 could enhance the infiltration of CD3+ CD4+ helper T and CD3+ CD8+ cytotoxic T cells in tumors, thus activating the tumor immune microenvironment. Moreover, HQ-30 possessed a benign toxicity profile (LD50 > 1000 mg/kg) and favorable pharmacokinetic properties (F = 57%). Taken together, HQ-30 is worthy of further investigation as a small molecule-based epigenetic modulator of tumor immunotherapy.
Asunto(s)
Antineoplásicos , Antígeno B7-H1 , Inhibidores de Histona Desacetilasas , Histona Desacetilasas , Inhibidores de Histona Desacetilasas/farmacología , Inhibidores de Histona Desacetilasas/química , Inhibidores de Histona Desacetilasas/síntesis química , Inhibidores de Histona Desacetilasas/farmacocinética , Humanos , Antígeno B7-H1/antagonistas & inhibidores , Antígeno B7-H1/metabolismo , Animales , Histona Desacetilasas/metabolismo , Antineoplásicos/farmacología , Antineoplásicos/química , Antineoplásicos/farmacocinética , Antineoplásicos/síntesis química , Ratones , Regulación hacia Abajo/efectos de los fármacos , Línea Celular Tumoral , Microambiente Tumoral/efectos de los fármacos , Relación Estructura-Actividad , Descubrimiento de Drogas , Catepsina B/antagonistas & inhibidores , Catepsina B/metabolismoRESUMEN
In this study, a novel series of histone deacetylases 6 (HDAC6) inhibitors containing polycyclic aromatic rings were discovered and evaluated for their pharmacological activities. The most potent compound 10c exhibited high HDAC6 inhibitory activity (IC50 = 261 nM) and excellent HDAC6 selectivity (SI = 109 for HDAC6 over HDAC3). 10c also showed decent antiproliferative activity in vitro with IC50 of 7.37-21.84 µM against four cancer cell lines, comparable to that of tubastatin A (average IC50 = 6.10 µM). Further mechanism studies revealed that 10c efficiently induced apoptosis and S-phase arrest in B16-F10 cells. In addition, 10c markedly increased the expression of acetylated-α-tubulin both in vitro and in vivo, without affecting the levels of acetylated-H3 (marker of HDAC1 inhibition). Furthermore, 10c (80 mg/kg) exhibited moderate antitumor efficacy in a melanoma tumour model with a tumour growth inhibition (TGI) of 32.9%, comparable to that (TGI = 31.3%) of tubastatin A. Importantly, the combination of 10c with NP19 (a small molecule PD-L1 inhibitor discovered by us before) decreased tumour burden substantially (TGI% = 60.1%) as compared to monotherapy groups. Moreover, the combination of 10c with NP19 enhanced the anti-tumour immune response, mediated by a decrease of PD-L1 expression levels and increased infiltration of anti-tumour CD8+ T cells in tumour tissues. Collectively, 10c represents a novel HDAC6 inhibitor deserving further investigation as a potential anti-cancer agent.
Asunto(s)
Linfocitos T CD8-positivos , Inhibidores de Histona Desacetilasas , Melanoma , Humanos , Linfocitos T CD8-positivos/metabolismo , Línea Celular Tumoral , Proliferación Celular , Histona Desacetilasa 6/antagonistas & inhibidores , Inhibidores de Histona Desacetilasas/farmacología , Melanoma/tratamiento farmacológicoRESUMEN
Through structural optimization and ring fusion strategy, we designed a series of novel imidazo[1,2-a]pyrazine derivatives as potential tubulin inhibitors. These compounds displayed potent anti-proliferative activities (micromolar to nanomolar) against a panel of cancer cell lines (including HepG-2, HCT-116, A549 and MDA-MB-231 cells). Among them, compound TB-25 exhibited the strongest inhibitory effects against HCT-116 cells with an IC50 of 23 nM. Mechanism studies revealed that TB-25 could effectively inhibit tubulin polymerization in vitro, and destroy the dynamic equilibrium of microtubules in HCT-116 cells. In addition, TB-25 dose-dependently induced G2/M phase cell cycle arrest and apoptosis in HCT-116 cells. Furthermore, TB-25 suppressed HCT-116 cell migration in a concentration-dependent manner. Finally, molecular docking showed that TB-25 fitted well in the colchicine binding site of tubulin and overlapped nicely with CA-4. Collectively, these results suggest that TB-25 represents a promising tubulin inhibitor deserving further investigation.
Asunto(s)
Moduladores de Tubulina , Tubulina (Proteína) , Moduladores de Tubulina/farmacología , Pirazinas/farmacología , Simulación del Acoplamiento MolecularRESUMEN
Overexpression of histone deacetylase 8 (HDAC8) is associated with various diseases such as cancer. Thus, compounds that can modulate HDAC8 levels have therapeutic potential for these diseases. Based on the proteolysis targeting chimera (PROTAC) strategy, we designed and synthesized a series of HDAC8 degraders by tethering an HDAC6/8 dual inhibitor with pomalidomide (a cereblon ligand). Among them, compound ZQ-23 exhibited significant and selective degradation of HDAC8 with DC50 of 147 nM and Dmax of 93%, and exhibited no effects on HDAC1 and HDAC3. Interestingly, we found that the degradation of target protein started at â¼2 h after treatment with ZQ-23 and the maximal degradation effect was achieved at 10 h. The HDAC8 level was partially recovered within 24 h. In addition, ZQ-23 had no degrading effects on HDAC1 and HDAC3 at all concentrations, but could dose-dependently increase the levels of acetylated SMC-3 (HDAC8 substrate). Mechanism study demonstrated that ZQ-23 degraded HDAC8 through the ubiquitin-protease pathway, rather than lysosome system. Collectively, these results suggest that ZQ-23 represents a novel PROTAC-based HDAC8 degrader worthy of further investigation.
Asunto(s)
Inhibidores de Histona Desacetilasas , Histona Desacetilasas , Inhibidores de Histona Desacetilasas/química , Inhibidores de Histona Desacetilasas/farmacología , Histona Desacetilasas/metabolismo , Proteolisis , Talidomida/análogos & derivados , Talidomida/farmacologíaRESUMEN
The activation of the cyclic GMP-AMP synthase-stimulator of interferon gene (STING) pathway has been associated with the pathogenesis of many autoimmune and inflammatory disorders, and small molecules targeting STING have emerged as a new therapeutic strategy for the treatment of these diseases. While several STING inhibitors have been identified with potent anti-inflammatory effects, we would like to explore STING degraders based on the proteolysis-targeting chimera (PROTAC) technology as an alternative strategy to target the STING pathway. Thus, we designed and synthesized a series of STING protein degraders based on a small-molecule STING inhibitor (C-170) and pomalidomide (a CRBN ligand). These compounds demonstrated moderate STING-degrading activities. Among them, SP23 achieved the highest degradation potency with a DC50 of 3.2 µM. Importantly, SP23 exerted high anti-inflammatory efficacy in a cisplatin-induced acute kidney injury mouse model by modulating the STING signaling pathway. Taken together, SP23 represents the first PROTAC degrader of STING deserving further investigation as a new anti-inflammatory agent.
Asunto(s)
Lesión Renal Aguda , Antiinflamatorios , Proteínas de la Membrana , Lesión Renal Aguda/inducido químicamente , Lesión Renal Aguda/tratamiento farmacológico , Proteínas Adaptadoras Transductoras de Señales , Animales , Antiinflamatorios/farmacología , Cisplatino , Interferones , Proteínas de la Membrana/antagonistas & inhibidores , Ratones , Proteolisis , Proteínas Recombinantes de Fusión/farmacologíaRESUMEN
Novel enzyme-triggerable cell penetrating peptide (ETCPP) dendrimers with a camptothecin (CPT) warhead were designed and synthesized based on an amphiphilic penetrating peptide (FKKFFRKLL, discovered by us before). Among the newly synthesized ETCPP dendrimer conjugates, BL_Oc-SS-CPT (a high-generation dendrimer) exhibited the highest activity with IC50s in the nanomolar range (31-747 nM) against a panel of cancer cells, which is 3-10 times better than that of CPT. BL_Oc-SS-CPT remained intact during transit to target cells and in normal tissues with a plasma half-life of 4.2 h, 2.3-fold longer than that of the monomer (1.8 h). Once reaching the tumor site, BL_Oc-SS-CPT gradually released CPT in the presence of excessive matrix metalloproteinase-2/9 and GSH in cancer cells. Importantly, BL_Oc-SS-CPT exhibited excellent in vivo tumor targeting capability and antitumor efficacy with benign toxicity profiles. Thus, the novel ETCPP dendrimer-based drug delivery system (e.g., BL_Oc-SS-CPT) represents a safe and effective strategy for targeted cancer therapy.
Asunto(s)
Camptotecina , Péptidos de Penetración Celular , Dendrímeros , Sistemas de Liberación de Medicamentos , Neoplasias , Antineoplásicos/administración & dosificación , Camptotecina/administración & dosificación , Camptotecina/farmacología , Línea Celular Tumoral , Péptidos de Penetración Celular/farmacología , Diseño de Fármacos , Humanos , Metaloproteinasa 2 de la Matriz , Neoplasias/tratamiento farmacológicoRESUMEN
A series of novel thieno[2,3-d]pyrimidine analogs were designed and synthesized as KRAS G12D inhibitors via combinatorial virtual screening approach. Most compounds exhibited potent antiproliferative activity on KRAS G12D mutated cancer cell lines (Panc1, SW1990 and CT26) with IC50 values in the low micromolar range. Among them, compound KD-8 showed the highest antiproliferative activity with an average IC50 of 2.1 µM against three KRAS G12D-mutated cells (Panc1, SW1990 and CT26). KD-8 decreased the active form of KRAS (KRAS-GTP) in KRAS G12D mutated cancer cell lines (CT26 and SW1990) but not in KRAS G13D mutated cancer cells (HCT116). Moreover, KD-8 down-regulated the phosphorylated Raf and Erk in CT26 and SW1990 cancer cell lines but not in HeLa cells (KRAS WT). The binding affinity of KD-8 was further confirmed by the isothermal titration calorimetry (ITC) assay in which KD-8 exhibited a KD of 33 nM for binding to KRAS G12D protein. In addition, KD-8 (40 mg/kg or 60 mg/kg) exhibited significant antitumor efficacy in a CT26 tumor model with a tumor growth inhibition (TGI) of 42% or 53% without causing apparent toxicity. Taken together the above results suggest that KD-8 is a promising KRAS G12D inhibitor deserving further investigation.