ACS Medicinal Chemistry Letters最新文献

The advent of immune checkpoint blockade therapy, exemplified by inhibitors targeting programmed cell death protein 1/programmed death-ligand 1 (PD-1/PD-L1) axis, has revolutionized the landscape of clinical oncology. Despite its remarkable success, therapeutic benefits remain limited to a subset of patients, highlighting the urgent need for more accurate methods of patient stratification. Conventional techniques for assessing PD-L1 expression, such as immunohistochemistry, provide static and localized information but lack the ability to capture whole-body distribution or temporal dynamics. In contrast, positron emission tomography (PET) offers a noninvasive approach for visualizing PD-L1 expression and disease burden in vivo. However, clinical translation of PD-L1-specific radiotracers has been hampered by suboptimal tumor accumulation and unfavorable pharmacokinetics. To address this limitation, a recent study established a disulfide-directed multicyclic peptide (DDMP) platform capable of generating high-affinity peptide ligands specifically designed for PD-L1 imaging and potential therapeutic applications.

DNA-encoded library (DEL) technology has emerged as a transformative platform for discovering chemical inducers of proximity (CIPs), addressing challenges in both degrader and non-degrader CIP development. This Microperspective analyzes the results of recent DEL technology screens (2021–2025) to enable medicinal chemistry programs, focusing on CIP development including CIP-focused DELs, DEL-derived ligands for proteins of interest (POIs) and E3 ligase in rational CIP design, and directly functional CIP identification. Finally, we address current limitations of DEL technology in CIP research and outline future directions. This Microperspective underscores DEL’s pivotal role in advancing CIP discovery, providing actionable insights for addressing “undruggable” targets and accelerating translational research in chemical biology and medicinal chemistry.

The increasing prevalence of multidrug-resistant bacteria necessitates the development of new antibacterial scaffolds with improved efficacy and safety. Thiosemicarbazones are known for their diverse antibacterial activities, and carbohydrate conjugation can enhance solubility and biocompatibility. In this study, a series of β-maltosyl thiosemicarbazones of substituted benzaldehydes (6a–u) were synthesized and evaluated for their antibacterial activity against representative Gram-(+) and Gram-(−) bacterial strains. These compounds displayed a wide range activity range with MIC of 0.78–400 μg mL^–1. Compounds 6b, 6c, 6f, 6i, 6n, 6q, and 6r were the most active, exhibiting MIC values as low as 0.78 μg mL^–1 against several pathogens and, in some cases, comparable to ciprofloxacin and vancomycin. Structure–activity relationship analysis revealed a strong dependence on aromatic substitution patterns. Analogues bearing electron-withdrawing substituents (Cl, Br, and NO₂) on the benzene ring showed markedly enhanced antibacterial activity, whereas electron-donating substituents (−OH, −OCH₃) generally reduced antibacterial activity. Enzyme inhibition assays identified compound 6f as a potent inhibitor of Staphylococcus aureus DNA gyrase and compound 6b as a strong topoisomerase IV inhibitor. Importantly, the most active compounds showed a low cytotoxicity toward WI-38 human fibroblast cells.

Hypertension, a major cardiovascular risk factor, is often treated with peptide-derived angiotensin-converting enzyme inhibitors (ACEi), which can have several side effects. This study examined a new alternative: isoindoline and isoindoline-1,3-dione derivatives as nonpeptide ACE inhibitors. The synthesis and testing of these compounds involved both in silico molecular docking studies and optimized in vitro inhibitory kinetic assays, along with acute toxicity tests in mice. isoindoline-1,3-dione, D-05, demonstrated the strongest ACE inhibition in vitro (IC₅₀ = 416.4 μM) and effectively bound to the enzyme’s catalytic active site in silico. Additionally, isoindoline-1,3-diones showed lower toxicity in mice (LD₅₀ > 1600 mg/kg) compared to isoindolines (LD₅₀ < 1000 mg/kg). This reduced toxicity is attributed to the presence of fewer reactive secondary metabolites. These promising results highlight the potential of isoindoline-1,3-diones as innovative nonpeptide ACE inhibitors and support further in vivo studies to verify their antihypertensive effects.

This patent provides novel macrocycle compounds that inhibit key mutants (G12D/G13D) of the KRAS oncogene, which is the most frequently mutated in human cancers. These compounds, along with their pharmaceutical compositions and protein complexes, are intended for the treatment of cancers driven by these mutations.

This patent describes novel prop-2-ynamide-derived epidermal growth factor receptor (EGFR) inhibitors, which selectively target EGFR exon20 insertion mutations. These EGFR inhibitors exhibit therapeutic potential for the treatment of nonsmall cell lung cancer (NSCLC) and other malignancies driven by EGFR mutations.

Protein Tyrosine Phosphatase 1B (PTP1B) is a crucial enzyme that significantly modulates insulin and leptin signaling, making it a highly promising target for the treatment of type 2 diabetes (T2D). We previously reported the synthesis and inhibitory activity of FC-114, an indole-fused glycyrrhetinic acid derivative that potently inhibits PTP1B. In this study, we synthesized four FC-114 conjugates with amino acids at the C30 position to enhance their inhibitory activity against PTP1B in vitro. The results indicated that incorporating glycine (compound 5a) and serine (compound 5d) substantially enhanced inhibitory activity against PTP1B, achieving up to 4-fold greater potency, with submicromolar IC₅₀ values of 0.64 and 0.54 μM, respectively. Inhibitory assessments of the short form (hPTP1B_1-285) and long form (hPTP1B_1-400) of PTP1B, along with enzymatic kinetics studies, molecular docking, and molecular dynamics analyses, suggested a mechanism consistent with uncompetitive inhibition, potentially involving a binding to the disordered C-terminal domain. Furthermore, both FC-114 conjugates with glycine (5a) and arginine (5b) significantly enhanced the mRNA expression of the GLUT4 receptor in C2C12 myoblast cells. Additionally, these compounds reduced glucose levels during the insulin tolerance test in streptozotocin-induced diabetic mice.

Ubiquitin-specific protease 1 (USP1) is a member of the deubiquitinating enzyme family that modulates the stability and biological activity of target proteins through the removal of ubiquitin modifications, thereby contributing to tumor development and resistance to anticancer therapies. This patent summary focuses on the design and optimization of a class of small-molecule inhibitors that exhibit high potency and selectivity toward USP1.

Niclosamide, an FDA-approved anthelmintic, functions as a mitochondrial uncoupler with promising anticancer potential, yet its efficacy remains limited, often ascribed to poor bioavailability. We identify a more fundamental constraint─its narrow therapeutic window arising from a biphasic mechanism that promotes uncoupling at low doses but inhibits respiration at higher doses. To overcome this limitation, we synthesized 30 niclosamide analogs, systematically profiled their mitochondrial responses using Seahorse MitoTox assay, and developed QSAR models to uncover structural determinants of efficacy and toxicity. Niclosamide exhibited a narrow uncoupling range (0.5–1 μM) beyond which respiration was suppressed. Several analogs, including Nic-2, Nic-8, Nic-40, and Nic-43, sustained uncoupling for up to 9 h at concentrations up to 10 μM, with some showing improved signal modulation and reduced cytotoxicity. QSAR analysis revealed that substitution electronic properties and ring-specific hydrophobicity are related to the therapeutic index. These findings expand niclosamide’s therapeutic window through rational scaffold tuning, enabling safer mitochondrial reprogramming strategies for cancer therapy.

α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors are tetrameric ionotropic glutamate receptors that mediate fast excitatory synaptic transmission in the brain and represent important therapeutic targets for neurological disorders. Positive allosteric modulators (PAMs) of AMPA receptors enhance rapid excitatory signaling by increasing receptor’s sensitivity to glutamate and have been widely explored as agents to improve cognitive function in central nervous system (CNS) diseases. Structural modification of 3,4-dihydro-2H-1,2,4-benzothiadiazine 1,1-dioxides (BTDs) analogs is a key strategy to develop potent AMPAR PAMs. A recent study reported a new pharmacomodulation strategy on the benzene ring of BTDs through systematic structure–activity relationship (SAR) optimization. This work led to the identification of compound 14o (BPAM363), which exhibits improved pharmacological properties, robust in vivo cognitive-enhancing and neuroprotective effects. These findings provide valuable insight for further development of AMPAR PAMs as therapeutic candidates for cognitive disorders.