ACS Medicinal Chemistry Letters最新文献

This patent describes KLF2-inducing compounds and related pharmaceutical compositions for the treatment of inflammatory diseases and endothelial dysfunction.

The c-MET kinase is a driver of many cancers, and as such, there are a number of small molecule inhibitors of this kinase approved for clinical use. In this Microperspective, we provide a structural overview of the molecular basis by which these drugs inhibit c-MET, focusing on key features contributing to activity, selectivity, and drug resistance. Where necessary, relevant crystal structures not publicly available were determined and are discussed here alongside existing structural data.

Downregulation of DNA damage repair genes has attracted considerable research attention recently due to the success of poly(ADP-ribose) polymerase inhibitors. Identification of additional targets and therapies that exploit synthetic lethality could greatly benefit cancer patients. Cyclin-dependent kinases 12 and 13 (CDK12 and CDK13), which regulate RNA polymerase II (RNA Pol II) and, therefore, gene transcription, represented promising therapeutic targets. Although several inhibitors for these kinases have been disclosed, few have progressed to the clinic. Most existing inhibitors utilize a covalent warhead to obtain potency and selectivity. In this study, we reported the design and development of a series of highly selective noncovalent inhibitors targeting CDK12 and 13. This campaign led to the identification of a lead compound exhibiting outstanding potency and favorable absorption, distribution, metabolism, and excretion profiles, as well as favorable pharmacokinetic properties, thereby demonstrating significant potential for therapeutic applications.

Canavan disease (CD) is an autosomal recessive genetic disorder caused by mutations in the ASPA gene, which encodes the enzyme aspartoacylase. These mutations lead to a deficient enzymatic activity and increased concentrations of its substrate, N-acetylaspartate (NAA), in the brain and other tissues. Aspartate N-acetyltransferase, encoded by the N-acetyltransferase 8-like (NAT8L) gene, catalyzes the biosynthesis of NAA from aspartate and acetyl-CoA. Therefore, inhibition of NAT8L has been implicated as a promising therapeutic strategy for CD by normalizing NAA levels in the brain. Our high throughput screening campaign followed by a rigorous hit validation process identified 2-(2-fluorophenoxy)-1-(3-((3-(thiophen-3-yl)-1,2,4-oxadiazol-5-yl)methyl)piperidin-1-yl)ethan-1-one (4a) as a low micromolar, noncarboxylic acid inhibitor of NAT8L. Subsequent structural optimization led to the discovery of two submicromolar NAT8L inhibitors. Although these inhibitors displayed high clearance in liver microsomes, the new scaffold, devoid of a carboxylic acid moiety, could potentially lead to potent and brain-penetrant NAT8L inhibitors through further molecular refinement.

The escalating threat of antibacterial resistance is a pressing global issue that highlights the urgent need for innovative antibiotics. In this regard, the recent discovery of evybactin─a nonribosomal depsipeptide antibiotic that selectively and effectively inhibits the growth of M. tuberculosis─is notable given its unique structure and mechanism of action. In a previous report, we described the first total synthesis of evybactin and a revision of the originally assigned structure. Building on this, we report here a series of structure–activity relationship studies with evybactin. In doing so, we synthesized a total of 21 novel evybactin analogues by performing an alanine scan and exploring multiple modifications, including variations of the ester-linked macrocycle, substitution of the formylated N-terminus, and removal of positively charged side chains. Our results provide valuable insights into the significance of certain amino acids and other structural features that underscore the potent antitubercular activity of this unique natural product.

Provided herein are novel compounds as MALT1 inhibitors, pharmaceutical compositions, use of such compounds in treating cancer, and processes for preparing such compounds.

Heparanase is the sole enzyme responsible for breaking down heparan sulfate within the extracellular matrix, and its overexpression is linked to human diseases. Despite heparanase being a promising drug target, most efforts have focused on substrate mimetics, which have failed clinical trials, highlighting the need for new inhibitor scaffolds. Here, we employed fragment-based drug design to explore a novel chemical space to develop small molecule inhibitors of heparanase. We used a crystallographic and computational approach to identify 31 fragments that bind heparanase; five of these inhibited heparanase in the micromolar range. One of these fragments underwent two cycles of fragment growing, which resulted in a compound with a 7-fold increased potency compared to the initial hit. The results from our fragment screen unveil untapped chemical space for heparanase inhibition, paving the way for the development of potent drug leads with the potential to transform the treatment of heparanase-related diseases.

Despite advancements in hit-finding technologies, many drug targets are considered difficult-to-drug (D2D) or difficult-to-ligand (D2L). Here, we present an analysis of 21 hit-finding campaigns across three research organizations within the Roche group, focusing on D2D and D2L targets. DNA-encoded library technology (DELT) was the most successful method in providing validated hits and lead series. High-throughput, covalent, and peptide screens also yielded progressable chemical matter in a substantial number of cases. In contrast, fragment and virtual screens, while effective in generating validated hits, demonstrated lower success rates. Stratifying targets into D2D and D2L categories provided a useful framework for estimating the likelihood of project success and informing additional screening strategies, with D2D targets showing higher rates of chemical enablement. Our findings indicate DELT as a valuable experimental tool for assessing ligandability and highlight the importance of informed integrated hit discovery by tailoring hit-finding strategies to target characteristics.

Provided herein are novel cyclopentapyrrole compounds as orexin receptor agonists, pharmaceutical compositions, use of such compounds in treating sleep disorders, namely, narcolepsy and hypersomnia, and processes for preparing such compounds.

Provided herein are novel compounds, pharmaceutical compositions, use of such compounds in treating hemoglobinopathies, and processes for preparing such compounds.