ACS Medicinal Chemistry Letters最新文献

Heat shock protein 90 (HSP90) is a promising target for oncology therapeutics. Over the past decades, several small molecule inhibitors have demonstrated significant antitumor activity in clinical trials. However, nearly all HSP90 inhibitors in clinical trials have failed due to toxicity or insufficient efficacy. By leveraging crystal structures and current knowledge, we synthesized and evaluated a series of novel derivatives with potent HSP90 inhibitory activity, optimized from resorcinol-based (2R, 4R)-4-phenylproline. These derivatives underwent SAR analysis, leading to the discovery of compounds 16t and 20m, which exhibit strong HSP90 binding affinity and antiproliferative effects against MCF-7, HCT116, SKBr3, K562, and A549 cell lines. Nevertheless, further optimization of derivatives 16t and 20m was required to enhance their oral bioavailability and isoform selectivity. Our findings provide valuable insights for the ongoing research into selective HSP90α inhibitors and lay a foundation for developing next-generation HSP90α inhibitors and antitumor agents.

Cdk5 regulatory associated protein 1-like 1 (CDKAL1) is one of the most reliable risk genes for type 2 diabetes mellitus (T2DM). Because CDKAL1 controls glucose-induced insulin secretion by K_ATP channel responsiveness and faithful decoding of Lys codons to prevent mistranslation in pancreatic β-cells, a rescuer of CDKAL1 defects is expected as a new antidiabetes drug. We found that eperisone analogs effectively rescued mistranslation in a MiaB-deficient Escherichia coli dual-luciferase reporter gene system (MiaB is a prokaryotic homologue of eukaryotic CDKAL1). Among them, compounds 1f and 1t demonstrated significant antihyperglycemic efficacy in an oral glucose tolerance test by subcutaneous administration in Wister rats, along with a significant enhancement of insulin secretion in the MIN6 insulinoma cell line without cytotoxicity. These results indicate that CDKAL1 could be a viable molecular target for a new anti-T2DM medication.

Cdk5 regulatory associated protein 1-like 1 (CDKAL1) is one of the most reliable risk genes for type 2 diabetes mellitus (T2DM). Because CDKAL1 controls glucose-induced insulin secretion by K_ATP channel responsiveness and faithful decoding of Lys codons to prevent mistranslation in pancreatic β-cells, a rescuer of CDKAL1 defects is expected as a new antidiabetes drug. We found that eperisone analogs effectively rescued mistranslation in a MiaB-deficient Escherichia coli dual-luciferase reporter gene system (MiaB is a prokaryotic homologue of eukaryotic CDKAL1). Among them, compounds 1f and 1t demonstrated significant antihyperglycemic efficacy in an oral glucose tolerance test by subcutaneous administration in Wister rats, along with a significant enhancement of insulin secretion in the MIN6 insulinoma cell line without cytotoxicity. These results indicate that CDKAL1 could be a viable molecular target for a new anti-T2DM medication.

Provided herein are novel bicyclic amines as CDK2 inhibitors, pharmaceutical compositions, use of such compounds in treating metastatic breast cancer or metastatic lung cancer and processes for preparing such compounds.

Provided herein are novel bicyclic amines as CDK2 inhibitors, pharmaceutical compositions, use of such compounds in treating metastatic breast cancer or metastatic lung cancer and processes for preparing such compounds.

Provided herein are novel carbocyclic phenylpyrrolidinone urea compounds as FPR2 agonists, pharmaceutical compositions, use of such compounds in treating atherosclerosis and heart failure, and processes for preparing such compounds.

Provided herein are novel carbocyclic phenylpyrrolidinone urea compounds as FPR2 agonists, pharmaceutical compositions, use of such compounds in treating atherosclerosis and heart failure, and processes for preparing such compounds.

Provided herein are novel 6-substituted-3-phenylisoindolin-1-ones as Cbl-b inhibitors, pharmaceutical compositions, use of such compounds in treating cancer, and processes for preparing such compounds.

New ubiquitin ligase (E3) ligands are crucial for developing proteolysis-targeting chimeras (PROTACs) to induce the degradation of a target protein. In this study, we developed a PROTAC using the antipsychotic drug clozapine as a new E3 ligand. First, a clozapine PROTAC targeting a model target HaloTag protein (Halo-PEG-Clozapine) was synthesized, and the PROTAC induced degradation of the HaloTag-fused protein in a cell culture system. Another clozapine PROTAC targeting the cancer therapeutic target estrogen receptor α (ERα) (Tamoxifen-PEG-Clozapine) was synthesized and induced degradation of the ERα protein in MCF-7 breast cancer cells. Experiments with inhibitors and siRNAs showed that Tamoxifen-PEG-Clozapine degraded ERα via a ubiquitin-proteasome system that uses the ubiquitin protein ligase E3 component N-recognin 5. These results indicate that clozapine is a promising E3 ligand that may expand the molecular design of PROTACs, contributing to the advancement of drug discovery by facilitating the degradation of disease-related proteins.

Provided herein are novel pyridine derivatives as 5-HT2A agonists, pharmaceutical compositions, use of such compounds in treating psychiatric disorders, and processes for preparing such compounds.