ACS Medicinal Chemistry Letters最新文献

Recent structure–activity relationships (SAR) were established around KU-177, the parent scaffold for an Hsp90/Aha1 small-molecule disruptor, which suggested that the central amide linker adopted a cis-amide conformation for the inhibitory activity. In this Letter, a series of analogues was synthesized to contain various amide bioisosteres, which were evaluated for their ability to disrupt Hsp90/Aha1 interactions. The inhibitory activity was determined with recombinant protein as well as co-immunoprecipitation experiments with cell lysates. The most efficacious scaffolds were assessed for solubility, metabolic stability, and permeability, where the most efficacious molecule was the sulfonamide-containing compound 44. New molecules emerged from this study and will be optimized in subsequent SAR campaigns.

To address the ongoing threat of SARS-CoV-2 and potential emergence of novel coronaviruses, we employed a comprehensive strategy to identify and synthesize inhibitors of coronavirus methyltransferases with chemical analogs of S-adenosylhomocysteine. Two analogs, designated 4h and 4p, inhibit both mouse hepatitis virus and SARS-CoV-2 replication. Compound 4p was most potent with half-maximal inhibition of biochemical activity at 0.2 μM and antiviral activity at ~20 μM. This compound also has low cytotoxicity and preferentially inhibits nsp14 over nsp16 and human methyltransferases. Furthermore, molecular docking based on a newly determined crystal structure of the apo nsp16-nsp10 complex predicts 4p occupies both the S-adenosylmethione and Gppp binding pockets of nsp14 and nsp16. Selectivity of 4p for nsp14 is likely due to enhanced structural stability of the nsp14 binding pocket relative to nsp16. These findings highlight SAH analogs as scaffolds for pan-coronavirus therapeutics and underscore the value of structure-guided design in antiviral drug discovery.

The invention discloses novel NOD-, LRR-, and pyrin domain-containing protein 3 (NLRP3) inhibitors featuring a 2H-pyrazolo[3,4-d]thiazole scaffold. These NLRP3 inhibitors exhibit significant potential as therapeutic candidates for neurodegenerative diseases, including Alzheimer’s disease and Parkinson’s disease.

N⁶-Methyladenosine methylation (m⁶A) is the most common type of RNA modification and is catalyzed primarily by the METTL3-METTL14 methyltransferase complex. METTL3 is considered a promising target for the treatment of acute myeloid leukemia (AML). However, only a few METTL3 inhibitors targeting the catalytic activity have been developed recently. Herein we report a series of novel METTL3 inhibitors bearing a pyridin-2(1H)-one moiety by structure-based drug design. Among these, compound 15 exhibits potent inhibitory activity against METTL3 (IC₅₀ = 50 nM). Compound 15 shows moderate metabolic stability in mouse and human liver microsomes. Meanwhile, in MV411 and SKM1 cell lines, compound 15 is able to potently inhibit cell proliferation. These results make compound 15 a promising lead compound for further optimization.

DNA-encoded libraries (DELs) have revolutionized hit identification in drug discovery by offering an accessible, versatile, and cost-effective alternative to traditional high-throughput screening (HTS). This perspective analyzes the results of recent DEL technology (DELT) screens (2020–2025) to enable medicinal chemistry programs, focusing on case studies where active series were generated from DEL, and distills key learnings and design principles for productive library construction. A notable trend is the productivity of 2-cycle DELs, which, despite their smaller size, consistently yield hits and have superior physicochemical properties, compared to 3-cycle libraries.

Chitinase-3-like protein 1 (CHI3L1), a glycoprotein implicated in inflammation and cancer, has emerged as a therapeutic target for glioblastoma (GBM). CHI3L1 contributes to tumor progression and immune evasion by promoting STAT3 signaling and mesenchymal transition. To identify small-molecule CHI3L1 inhibitors, a structure-based 3D pharmacophore model was developed and applied to virtually screen over 4.4 million compounds. We selected 35 candidates for experimental evaluation. Binding validation via MST confirmed dose-dependent CHI3L1 interactions for two compounds, 8 and 39, with dissociation constants (K_d) of 6.8 μM and 22 μM, respectively. These CHI3L1 affinities were further supported by SPR-based screening. In 3D GBM spheroid models, compound 8 reduced spheroid viability and attenuated phospho-STAT3 levels, consistent with CHI3L1 pathway disruption. Compared to the previously reported CHI3L1 inhibitors, compound 8 demonstrates superior CNS pharmacokinetics, inhibition of STAT3 and angiogenesis, and enhanced efficacy in GBM spheroids, establishing it as a more translationally viable scaffold.

A series of carboxyamido-propanyl analogs is described as antiviral agents for inhibition of the replication of hRSV and hMPV. Human Respiratory Syncytial Virus (hRSV, RSV) belongs to the family Paramyxoviridae and the subfamily Pneumovirinae that are significant human and animal pathogens. After hRSV, hMPV (metapneumovirus) is the second most common cause of lower respiratory infection in young children. Therefore, inhibition of hRSV and hMPV is an important approach for the potential treatment of respiratory viral infections.

Fibrodysplasia ossificans progressiva (FOP) is a rare autosomal-dominant disease leading to progressive soft tissue heterotopic ossification (HO) with no curative treatment available to date. It is caused by gain-of-function mutations in the activin A type-1 receptor ACVR1/ALK2, a member of the bone morphogenetic protein (BMP) type I receptor family. Most recent clinical trials in FOP have adopted for the first time on-target therapies to normalize the aberrant ALK2 receptor activity. Here we describe the discovery and preclinical characterization of zilurgisertib, a novel small-molecule inhibitor of ALK2 kinase with high biochemical and cellular potency, selectivity over other BMP and TGFβ signaling receptor kinases, and excellent oral bioavailability in preclinical species. Zilurgisertib fully suppresses HO in a pediatric mouse model of injury-induced FOP and therefore holds great potential as a novel targeted disease-modifying therapy for FOP. The candidate is being evaluated in clinical trials.

Epigenetic dysregulation, particularly aberrant histone methylation orchestrated by histone methyltransferases (HMTs), is a fundamental driver of hepatocellular carcinoma (HCC). Among these HMTs, H3K9-specific methyltransferase G9a is markedly upregulated and promotes tumorigenesis. However, current G9a inhibitors lack sufficient selectivity and potency. Here, we identified compound 1071, a novel selective G9a inhibitor with a distinct chemical scaffold, which demonstrates superior cellular activity compared with the existing G9a inhibitor UNC0638. Mechanistically, compound 1071 reduces H3K9me2 levels and modulates the expression of key G9a targets, including p21, FOXO1, and PD-L1. Moreover, compound 1071 exhibits potent antitumor activity in both subcutaneous and c-Myc-driven HCC models, outperforming the first-line drug sorafenib without significant toxicity. This study establishes compound 1071 as a promising lead for G9a-targeted HCC therapy, advancing epigenetic drug discovery.

This patent application discloses a series of bicyclic peptides targeting the Interleukin-23 receptor (IL-23R), as represented by Formula I. These peptides exhibit significant therapeutic potential, particularly for the treatment of inflammatory conditions, and hold promise for benefiting patients with inflammatory bowel disease (IBD).