ACS Medicinal Chemistry Letters最新文献

Inhibition of histone deacetylase 6 (HDAC6) has become a promising therapeutic strategy for central nervous system diseases. To address the metabolic instability of our previously discovered brain-penetrant HDAC6 inhibitor 5, herein the identification of metabolic sites and structural optimization based on 5 were carried out. The most potent compound, 8k, potently and selectively inhibited HDAC6 (IC₅₀ = 4.0 nM; >176-fold selectivity) and exhibited a 2-fold longer half-life in rat liver microsomes (T_1/2 = 29.49 min) than 5. It stabilized the HDAC6 complex in silico and increased the level of acetylated α-tubulin in SH-SY5Y cells. In vivo, 8k significantly reduced cerebral infarction (from 32.87% to 13.13%) in the rat MCAO model. These results demonstrate that 8k is a metabolically stable, highly selective HDAC6 inhibitor with compelling neuroprotective efficacy, warranting its further development for ischemic stroke.

Fibroblast activation protein (FAP), which is overexpressed in malignant epithelial tumors, represents a key therapeutic and diagnostic target. This study reports the development and evaluation of a novel FAP-targeted SPECT radiotracer, [^99mTc]4. The precursor was synthesized and labeled with ^99mTc using a one-pot labeling procedure, yielding a radiochemical purity exceeding 95%. The tracer exhibited high hydrophilicity (log P = −1.366 ± 0.004) and demonstrated excellent stability in PBS and serum over 7 h. In vitro, [^99mTc]4 showed specific uptake and rapid internalization in FAP-positive cells, which could be effectively blocked by competitive FAP inhibitors. In vivo SPECT/CT imaging and biodistribution studies in U87MG tumor-bearing mice revealed modest and specific tumor uptake, which was significantly reduced by co-injection with FAPI-04, confirming FAP-mediated targeting. These findings indicate that [^99mTc]4 is a highly promising candidate for noninvasive SPECT imaging of FAP expression in tumors, providing a valuable tool for tumor diagnosis and therapeutic monitoring.

Cyclic GMP-AMP synthase (cGAS) is a key component of the cGAS-STING innate immunity pathway’s response to pathogens. Activation of cGAS triggers a cascade resulting in an increase of proinflammatory mediators, suggesting cGAS inhibition as an attractive therapeutic approach for a variety of autoimmune and neurodegenerative diseases. The medicinal chemistry optimization of tetrahydrocarboline cGAS inhibitor 3 was performed with particular emphasis on mitigating hERG activity and improving bioavailability. Meticulous control of polarity was found to be essential to access acceptable in vitro permeability and stability profiles while mitigating hERG inhibition. Compound 26 was identified as a potent cGAS inhibitor displaying favorable hERG and mouse pharmacokinetic (PK) profiles.

The cGAS-STING pathway is a critical component of the innate immune system, responsible for detecting cytosolic DNA and triggering inflammatory signaling. While essential for host defense, aberrant activation of this pathway is linked to a range of inflammatory and autoimmune disorders. Consequently, STING has emerged as a compelling therapeutic target. Herein we report the development of the first reversible covalent STING inhibitor, i.e., UM-203 which employs an alkyne-thiazole warhead. UM-203 inhibits STING-dependent signaling in both mouse and human systems. Notably, UM-203 maintains activity against the most prevalent human STING variant (R232), effectively suppresses STING signaling in primary human CD14+ monocytes, and exhibits moderate metabolic stability. Collectively, these findings highlight UM-203 as a promising scaffold for the development of therapeutics targeting STING-driven inflammatory and autoimmune diseases.

The global rise of multidrug-resistant bacteria has prompted an urgent need for new antibiotics, yet resistance continues to outpace discovery due to Gram-negative barriers, drug permeability issues, and limited industry investment. In this study, we synthesized a series of 1-hydroxypyridin-2(1H)-one derivatives targeting Pseudomonas aeruginosa for analyses of antibacterial efficacy. Among these, LP07 displayed potent antibacterial activity across multiple strains, enhanced by subinhibitory colistin. Scanning electron microscopy suggested membrane-associated morphological changes, including surface collapse, shrinkage, and irregular cell shape, consistent with bactericidal effects. Safety profiling showed low CYP inhibition, minimal hERG liability, and no mammalian cytotoxicity. Taken together, LP07’s whole-cell activity and observed membrane effects support its promise as a lead for further optimization.

The dysregulation of the mesenchymal-epithelial transition factor (c-MET) signaling pathway is linked to the development and drug resistance of non-small cell lung cancer (NSCLC), highlighting the need for small-molecule inhibitors targeting c-MET. In this study, we identified six potential c-MET inhibitors from a compound library using structure-based and AI-based virtual screening. Four compounds demonstrated c-MET inhibitory activity, with compound 2 exhibiting potent inhibition at an IC₅₀ of 40.1 nM. Further studies showed that compound 2 effectively inhibited NSCLC cell proliferation, comparable to that of positive controls. ADMET predictions indicate favorable drug-like properties, suggesting its potential as a novel c-MET inhibitor. Molecular dynamics simulations revealed that compound 2 stabilizes its conformation through interactions with Ala1221, Pro1158, and Lys1110, providing valuable insights for further drug development.

Tubulin inhibitors, such as taxanes and vinca alkaloids, target the microtubule and are limited by multidrug resistance, toxicity, and myelosuppression. Phenylahistin derivatives, a natural marine product, exert an anticancer effect by depolymerizing microtubules and disrupting vasculature and treat chemotherapy-induced neutropenia by activating GEF-H1, which binds to the colchicine site. To discover new phenylahistin derivatives, 24 novel furan-type phenylahistin derivatives were designed and synthesized by replacing the 1,3-imidazol-4-yl group with furan-type substitutions. Antitumor proliferation screening showed that 10u (16 nM) and 10v (21 nM) were more effective than plinabulin (26 nM). Compounds 10u and 10v induced cell death through the mitochondrial pathway. Compounds 10u and 10v also induced cancer cell apoptosis by inhibiting Bcl-2, upregulating P53, reducing mitochondrial membrane potential, and elevating ROS levels, disrupting microtubule networks, inducing G2/M arrest, and promoting apoptosis via caspase-3 activation. And molecular docking revealed that the furan-based derivatives formed important bonds with β-tubulin.

The 5-HT2A and 5-HT2C receptors are key therapeutic targets for CNS disorders. We investigated whether a nonhallucinogenic dual 5-HT2A/5-HT2C agonist could offer novel treatment potential. Large screening of in-house structurally diverse compounds revealed centhaquin, an FDA-approved hypovolemic shock drug, as a selective 5-HT2C agonist (EC50: 35 nM). We then synthesized 22 aza-aryl analogs with modified piperazine groups, and identified two dual agonists, 3ci and 3dh (EC50 < 1 μM), with no 5-HT2B activity up to 10 μM. Molecular docking highlighted critical interactions with Ser159 (5-HT2A) and Ser138 (5-HT2C) on the upper side of the orthosteric binding pocket. Pharmacokinetic studies in mice demonstrated that 3ci was rapidly absorbed in the plasma and brain (T_max = 0.08 h; C_max = 936.4 ng/mL plasma, 2446.8 ng/g brain). Both compounds (3ci and 3dh, 20 mg/kg, i.p.) triggered a head-twitch response but were less potent than the hallucinogenic control 2,5-dimethoxy-4-iodoamphetamine, suggesting a reduced hallucinogenic liability. These results highlight 3ci as a promising lead for developing 5-HT2A/2C dual agonists to treat CNS disorders.

Hypertension is implicated in the highest number of deaths worldwide. Despite awareness of its complications and the availability of several antihypertensive treatments, hypertension remains poorly controlled, often due to adverse effects that can hinder adherence. Angiotensin-converting enzyme (ACE), a key enzyme of the renin-angiotensin system (RAS), is an important therapeutic target. Bioactive peptides have been extensively researched for their biological activities, including their antihypertensive potential. Here, we describe two novel peptides, MSFLEHFLELK (PepDB_AHP1) and VWTNCYHLYPAH (PepDB_AHP4). Both peptides interact with residues at ACE’s active site, such as His353, Ala354, and Val380. IC₅₀ values were 331.2 and 88.63 μM, respectively. These peptides may serve as models for further optimization aimed at the development of novel ACE-inhibitory drugs.