ACS Medicinal Chemistry Letters最新文献

Endoplasmic reticulum aminopeptidase 1 (ERAP1) cleaves the N-terminal amino acids of peptides, which can then bind onto major histocompatibility class I (MHC-I) molecules for presentation onto the cell surface, driving the activation of adaptive immune responses. In cancer, overtrimming of mature antigenic peptides can reduce cytotoxic T-cell responses, and ERAP1 can generate self-antigenic peptides which contribute to autoimmune cellular responses. Therefore, modulation of ERAP1 activity has potential therapeutic indications for cancer immunotherapy and in autoimmune disease. Herein we describe the hit-to-lead optimization of a series of cyclohexyl acid ERAP1 inhibitors, found by X-ray crystallography to bind at an allosteric regulatory site. Structure-based drug design enabled a >1,000-fold increase in ERAP1 enzymatic and cellular activity, resulting in potent and selective tool molecules. For lead compound 7, rat pharmacokinetic properties showed moderate unbound clearance and oral bioavailability, thus highlighting the promise of the series for further optimization.

FGFR has been considered a crucial oncogenic driver and promising target for cancer therapy. Herein, we reported the design and synthesis of 3-amino-N-(3,5-dihydroxyphenyl)-6-methylpyrazine-2-carboxamide derivatives as novel FGFR inhibitors. SAR exploration led to the identification of 18i as a pan-FGFR inhibitor with favorable in vitro activity against FGFR1–4. Moreover, 18i blocked the activation of FGFR and downstream signaling pathways at the submicromolar level and exhibited potent antitumor activity in multiple cancer cell lines with FGFR abnormalities. Molecular docking was performed to investigate the possible binding modes of 18i within the binding site of FGFR2. These results suggest that compound 18i is a promising candidate for further drug discovery.

FGFR has been considered a crucial oncogenic driver and promising target for cancer therapy. Herein, we reported the design and synthesis of 3-amino-N-(3,5-dihydroxyphenyl)-6-methylpyrazine-2-carboxamide derivatives as novel FGFR inhibitors. SAR exploration led to the identification of 18i as a pan-FGFR inhibitor with favorable in vitro activity against FGFR1-4. Moreover, 18i blocked the activation of FGFR and downstream signaling pathways at the submicromolar level and exhibited potent antitumor activity in multiple cancer cell lines with FGFR abnormalities. Molecular docking was performed to investigate the possible binding modes of 18i within the binding site of FGFR2. These results suggest that compound 18i is a promising candidate for further drug discovery.

p53 is a potent transcription factor that is crucial in regulating cellular responses to stress. Mutations in the TP53 gene are found in >50% of human cancers, predominantly occurring in the DNA-binding domain (amino acids 94-292). The Y220C mutation accounts for 1.8% of all of the TP53 mutations and produces a thermally unstable protein. Rezatapopt (also known as PC14586) is the first small-molecule p53 Y220C reactivator being evaluated in clinical trials. Rezatapopt was specifically designed to tightly bind to a pocket created by the TP53 Y220C mutation. By stabilization of the p53 protein structure, rezatapopt restores p53 tumor suppressor functions. In mouse models with established human tumor xenografts harboring the TP53 Y220C mutation, rezatapopt demonstrated tumor inhibition and regression at well-tolerated doses. In Phase 1 clinical trials, rezatapopt demonstrated a favorable safety profile within the efficacious dose range and showed single-agent efficacy in heavily pretreated patients with various TP53 Y220C mutant solid tumors.

Novel azaspirooctane-carboxylates are described for potential treatment of Alzheimer’s disease and Parkinson’s disease, among other conditions.

Hyperoxaluria is caused by increased urinary excretion of oxalate leading to the formation of calcium oxalate (CaOx) stones. The lack of effective management strategies for hyperoxaluria prompted us to investigate molecular mimics as stone inhibitors, a strategy that we previously used successfully to discover small molecule inhibitors of l-cystine crystallization for the prevention of l-cystine stone formation in cystinuria. Herein, we report the discovery of l-lysine dioxalate (LH1513), a novel dioxamate derivative, as a more potent inhibitor of CaOx crystallization than citrate and pyruvate. Such inhibition was corroborated by in situ atomic force microscopy (AFM) measurements of crystal growth rates at the microscopic length scale. A triester prodrug of LH1513 was found to have sufficient oral bioavailability for a preliminary in vivo study demonstrating efficacy in preventing urinary CaOx crystal formation in an Agxt-knockout mouse model for hyperoxaluria.

Novel azaspirooctane-carboxylates are described for potential treatment of Alzheimer's disease and Parkinson's disease, among other conditions.

Hyperoxaluria is caused by increased urinary excretion of oxalate leading to the formation of calcium oxalate (CaOx) stones. The lack of effective management strategies for hyperoxaluria prompted us to investigate molecular mimics as stone inhibitors, a strategy that we previously used successfully to discover small molecule inhibitors of l-cystine crystallization for the prevention of l-cystine stone formation in cystinuria. Herein, we report the discovery of l-lysine dioxalate (LH1513), a novel dioxamate derivative, as a more potent inhibitor of CaOx crystallization than citrate and pyruvate. Such inhibition was corroborated by in situ atomic force microscopy (AFM) measurements of crystal growth rates at the microscopic length scale. A triester prodrug of LH1513 was found to have sufficient oral bioavailability for a preliminary in vivo study demonstrating efficacy in preventing urinary CaOx crystal formation in an Agxt-knockout mouse model for hyperoxaluria.