搜索结果：ACS medicinal chemistry letters

Analogues of tadalafil, an FDA-approved inhibitor of human phosphodiesterase 5, have been reported to block the growth of human Plasmodium falciparum in vitro. Herein, we synthesized and evaluated 56 tadalafil analogues prepared as pure diastereomers. Some of the analogues showed potent antiplasmodial activity at nanomolar concentrations with selectivity indices >20-250 in vitro. Compound 33 was the most potent analogue, with an IC50 of 80 nM against cultured parasites and an IC50 > 20 μM on HeLa cells, resulting in a selectivity index >250. Several compounds were tested for potential inhibition of synthetic malaria pigment (β-hematin) formation and PfIspD (2-C-methyl-d-erythritol 4-phosphate cytidylyltransferase); it is possible that compounds 2 and 4 act by disrupting hemozoin formation whereas none of the tested analogues acted as PfIspD inhibitors. Metabolomic profiling revealed that some analogues strongly affect hemoglobin catabolism yet principal component analysis grouped them separately, suggesting differences in their antiplasmodial mechanisms of action.

Heterobifunctional proteolysis targeting chimeras (PROTACs) are proven to degrade disease-causing proteins, and many PROTACs have already entered into clinical trials. The majority of these PROTACs recruit cereblon (CRBN) or von Hippel-Lindau (VHL) substrate receptors of cullin RING E3 ubiquitin ligases, but there remains a need for alternative E3 ligase ligands. In this study, we enable DDB1 as an E3 ligase adapter protein for PROTAC drug discovery, describe a DNA-encoded library (DEL) ligand discovery campaign, and report the identification of a novel DDB1 ligand. Structure-guided modifications allowed DDB1 ligands to be developed from the initial DEL hit with nanomolar potency. Biochemical assays, cellular target engagement, and X-ray crystallography analysis demonstrated binding of the ligand to a unique pocket within DDB1. This chemical series furthers our understanding of ligand binding pockets within DDB1 and expands the repertoire of small molecules that may be suitable for the incorporation into PROTACs.

Oral bioavailability of PROTACs, which often fall outside the Rule-of-Five space, is still not perfectly understood. Thus, the design of orally bioavailable PROTACs remains challenging. Chameleonicity, the ability of a compound to adapt its conformation to different environments (solvent or membrane), has been suggested as a key molecular property. Here, using a diverse set of PROTACs from our portfolio, we evaluate whether published guidelines including predicted or experimental chameleonicity descriptors could refine AstraZeneca's internal guidelines for designing orally absorbed PROTACs. We did not find such a trend. Instead, reducing the efflux ratio in Caco-2 cells emerged as a useful addition to our guidelines.

Proteolysis-targeting chimeras (PROTACs) represent a promising modality for targeted protein degradation, yet their structural complexity complicates systematic design and analysis. Bellerophon is a new computational tool that automatically decomposes PROTACs into their warhead, linker, and E3 ligase ligand directly from molecular structure. By enabling automated and standardized decomposition of degraders, the tool facilitates drug design at different levels: Bellerophon demonstrated versatility for moiety replacement (ARV-110), large-scale annotation (PROTAC-DB) and linker analysis (IRAK4 data set). The tool is freely available through a user-friendly web interface, with open-source code to encourage transparency and collaborative development in chemical biology and medicinal chemistry.

Targeted protein degradation (TPD) via the ubiquitin-proteasome system (UPS) is a rapidly advancing drug discovery strategy that enables the selective elimination of pathogenic proteins using small molecules. Here, we report the discovery of BRD4-selective monovalent direct degraders acting through DCAF11, identified by ultrahigh-throughput screening and subsequently optimized through a structure-guided medicinal chemistry campaign. Structure-activity relationship (SAR) studies support a direct degrader mechanism and culminated in the identification of the orally bioavailable compound PLX-4104. In vitro, PLX-4104 induces rapid, complete, and selective degradation of BRD4 and exhibits potent antiproliferative activity in acute myeloid leukemia (AML) models. In vivo, PLX-4104 treatment resulted in complete tumor regression in the AML MV-4-11 xenograft model. Collectively, this lays the groundwork for the rational development of monovalent direct degraders with applications extending beyond BRD4.

DNA-encoded library (DEL) screening enables identification of small-molecule binders from libraries containing billions of compounds, yet much of the resulting structure-activity relationship (SAR) information remains underutilized. Here, we describe DEL2PH4, an automated ligand-based workflow that converts DEL screening data into three-dimensional pharmacophore models by integrating statistically enriched compounds with structurally related unenriched analogs, which serve as negative examples during model construction. The resulting pharmacophores capture consensus interaction features across DEL families and enable the extraction of actionable 3D SAR information from primary DEL screening data, independent of resynthesis or activity measurements. Application to a MerTK kinase DEL screen demonstrates strong enrichment of positives over decoy molecules in retrospective benchmarking, recovery of known experimentally validated actives from external data sets, and consistency with experimentally determined X-ray binding modes. DEL2PH4 provides a general strategy for translating DEL screening outputs into interpretable 3D models that support virtual screening, scaffold hopping, and medicinal chemistry optimization.

Casein kinase 2 (CK2), comprising the catalytic subunits CK2α and CK2α', is a highly conserved and constitutively active serine/threonine kinase that is implicated in oncogenic signaling and tumor maintenance, making it an attractive therapeutic target. We report a medicinal chemistry campaign that delivered an imidazotriazine pan-CK2 series culminating in BMS-135 and its phosphate prodrug BMS-159. Structure-guided design enabled a scaffold hop from imidazopyridazine to imidazotriazine that improved kinome selectivity while preserving critical hinge and Lys68 interactions. Iterative SAR optimization mitigated hERG liability by modulating distal basicity and enhanced metabolic stability via a C8 N-ethyl substitution that blocked N-dealkylation, delivering BMS-135 as a sub-nanomolar CK2 inhibitor with favorable ADMET properties and robust antitumor efficacy across xenograft and patient-derived xenograft models. Subsequent pharmaceutical optimization through a prodrug strategy afforded BMS-159, which markedly improved solubility and enabled oral delivery of the parent with acceptable bioavailability and pharmacokinetic properties suitable for further development.

Efficient routes to libraries of nonpeptidic macrocycles facilitate drug discovery. Monomers presenting hydrazine and acetal groups separated by a triazine ring and glycine linker dimerize efficiently to yield homodimers (when one monomer is employed) or a mixture of two homodimers and a heterodimer (when two monomers are used). Descriptively, dimerization proceeds quantitatively. The solvent and byproducts are volatile, eliminating the need for additional purification. To evaluate the functional group tolerances of this chemistry, a library of 1275 compounds was created from 50 monomers. Liquid chromatography-mass spectrometry validates the integrity of the library. All reactions yield macrocycles, but under the reaction conditions employed, partial hydrolysis is observed with three ester-containing monomers. Cleavage of a naphthylethyl group is observed for another. Monomers containing a BOC-protected amine, a tert-butyl ester or tert-butyl ether undergo quantitative deprotection as desired. Reaction of three monomers (wherein one is subject to partial hydrolysis) gives rise to the expected 10 macrocycles.

Targeted protein degradation continues to reshape therapeutic strategy, yet the structural constraints of cereblon (CRBN) ligand chemistry limit broader application. Patent application WO 2026/043898 A1 discloses acyclic glutarimide-based precursors that undergo in situ cyclization to generate active degraders. This prodrug-like strategy enables temporally controlled CRBN engagement, enhances conjugation compatibility, and expands the degrader design space across oncology and related indications.

The Viewpoint addresses the importance of correct designations of stereochemistry in chiral drugs. Sources of confusion typically arise from merging disparate concepts such as handedness, configuration, and chiroptical properties. This Viewpoint recommends the consistent use of configurational labeling, while avoiding ambiguous and context-dependent nomenclature.

The glucagon peptide 1 receptor (GLP-1R), a class-B-type G protein-coupled receptor (GPCR), is a key therapeutic target for many metabolic disorders, including obesity and type 2 diabetes, due to its central role in glucose homeostasis and insulin secretion. Despite its pharmacological importance, studying the binding kinetics of its multidomain engagement with peptide ligands remains a challenge using purified receptor systems. The isolated forms fail to capture the dynamic behavior of membrane-bound GPCRs in a physiologically relevant context. A deeper understanding of the interaction kinetics of agonist and antagonist binding to GLP-1R domains is essential for rational drug design, as the activation of the receptor depends on distinct binding modes that modulate downstream signaling efficacy. Here we employ surface plasmon resonance microscopy (SPRM) on HEK293T cells overexpressing GLP-1R to visualize and quantify the label-free kinetic interactions of ligands on whole single cells in real time. Using three different agonists (GLP-1, liraglutide, exendin-4) and one antagonist (exendin-9), we demonstrate that the agonists exhibit a two-mode/bivalent binding behavior with C-terminal engagement of the extracellular domain (ECD) and N-terminal engagement of the transmembrane domain (TMD). In contrast, the antagonist exendin-9 binds with a single mode, exclusively to the ECD. Importantly, SPRM resolves not only the presence of dual-domain engagement but also the stability and heterogeneity of these interactions, enabling discrimination between full and partial agonism. Notably, liraglutide displays the highest interaction affinity and the greatest amount of activation through TMD binding, which agrees with its known structural optimization and superior therapeutic performance. This study highlights SPRM as a powerful, label-free platform for probing the on-cell binding kinetics of GPCR interactions with peptides, providing quantitative insights into the activation efficiency of agonists and selectivity of antagonists in ways conventional receptor assays cannot.

Provided herein are novel compounds as PTPN2 inhibitors, pharmaceutical compositions, use of such compounds in treating cancer, and processes for preparing such compounds.

The global spread of multidrug-resistant bacterial strains poses a major threat to public health and underscores the urgent need for new antibacterial chemotypes. We report here the discovery and optimization of a novel scaffold, N-(benzothiazol-2-yl)-trichloroacetamidine, with potent activity against multidrug-resistant Staphylococcus aureus. Focused phenotypic screening of 304 N-(azol-2-yl)-imidamide derivatives identified N-(benzothiazol-2-yl)-trichloroacetamidine as a hit. Subsequent optimization through the synthesis of 55 analogues across five series, combined with SAR studies, yielded four lead compounds, displaying strong Gram-positive selectivity and high potency against clinically isolated S. aureus strains. Toxicity evaluation in human cells confirmed a favorable safety profile, while resistance assays indicated low likelihood of bacterial intrinsic resistance. Pharmacokinetic studies in mice demonstrated that lead compound 18 possesses desirable in vivo properties, including a 3 h half-life, good systemic exposure, and no observable toxicity. Collectively, these findings establish N-(benzothiazol-2-yl)-trichloroacetamidines as a promising new class of antibacterial agents for combating multidrug-resistant S. aureus infections.

This patent describes compounds and pharmaceutical compositions thereof for inhibiting PDE4 and treatment of disease.

The Hippo-YAP pathway has emerged as a central regulator of tissue growth and oncogenesis, yet remains resistant to conventional pharmacological targeting. Patent application WO 2026/044133 A1 discloses small-molecule strategies that modulate YAP activity through transcriptional complex disruption and protein stability interference. Robust cellular validation across YAP-dependent cancer models establishes proof of concept for tractable YAP inhibition, with implications spanning oncology and regenerative medicine.

Targeted covalent inhibitors (TCIs), a class of pharmaceuticals that specifically recognize disease-related proteins and form covalent bonds for precise therapy, still suffer from side effects and diminished efficacy due to poor tumor cell specificity. To address this, we present a new cell/protein "Double Insurance" targeting strategy through constructing a novel antibody-TCI conjugate (Ab-TCI), which comprises a monoclonal antibody (Loncastuximab), a TCI (As-Ibt) for Bruton's tyrosine kinase (BTK), and between them an arsenic-thiol bond as a new cleavable linker. This Ab-TCI enables B-cell lymphoma cell recognition, internalization, and release of As-Ibt by intracellular GSH, efficiently inhibiting BTK, and effectively suppressing the growth of xenograft tumors. To our knowledge, this is the first Ab-TCI enabling simultaneous dual targeting capabilities for cancer cells and kinase, achieving a remarkable improvement in drug efficacy. New potent dual-targeting Ab-TCIs could be inspired by integrating different FDA approved TCIs and antibodies through our strategy for cancer treatment.

Inhibitors of voltage-gated sodium channel 1.8 (NaV1.8) are anticipated to provide opioid-free treatment for acute pain and potentially chronic neuropathic pain. Herein, we report on the discovery of a novel series of NaV1.8 inhibitors characterized by high selectivity over other sodium channels. Utilizing a pharmacophore model trained on literature data, we identified the initial hit compound 1 through virtual screening. During the hit-to-lead optimization phase, we improved the potency and clearance of the lead compounds. Structural modifications and control of lipophilicity and other physicochemical parameters resulted in a favorable in vitro safety and drug-drug interaction profile for compound 24. Key to optimizing the clearance was the identification of a metabolic hotspot via metabolite identification (MetID) experiments. The lead compound 24 exhibited a long in vivo half-life and high exposure (K p,uu) in the pain-relevant target tissue (DRG) in rat PK studies. These findings highlight potential of these compounds for further optimization as nonopioid therapeutics.

The tumor microenvironment is characterized by conditions that frequently lead to immunosuppression, allowing tumors to escape immune surveillance and potentially contributing to resistance to immuno-oncology therapeutics. A potential strategy for combination therapy with checkpoint inhibitors is to target the A2A and A2B receptors with a dual antagonist that could rescue T cells from adenosine-mediated suppression. Herein, we describe efforts toward highly potent and selective A2A/A2B dual receptor antagonists with improved pharmacokinetic and solubility profiles compared to initial lead compounds. We discovered that a 1,3-cyclobutane linker between our triazoloquinazoline core and a pendant aryl substituent decorated with a tertiary carbinamine provided a desirable balance of potency and physicochemical properties. Our lead molecule 34 demonstrated an exceptional effective half-life across multiple species. Chemistry advances guided by high-throughput experimentation (HTE) facilitated efficient, late-stage access to complex derivatives in this series.

The design of novel small molecules with high selectivity for anticancer action remains a priority in the development of chemotherapy. A combination of the "privileged scaffold" of the chroman-4-one with rigid spirocyclic structures offers a strategy for modulating the specificity of action. A collection of 28 spirocyclohexane-chroman-4-one derivatives was screened using fluorescence cell coculture test, and compound 1 was selective in the breast cancer model. Structure-activity relationship analysis was performed within three rounds of optimization with rational synthesis of derivatives. Reduction of the carbonyl group to hydroxyl and incorporation of a dioxolane group into the spirocyclohexane ring reduced toxicity toward noncancerous VA13 and MCF10A cells. The lead compound 42 with this elaborated structure exhibited cytotoxicity against MCF7 cells (IC50 ≈ 3.8 μM) and remained significantly less cytotoxic to both noncancerous cells. It highlights the potential of spirocyclic-fused chroman-4-ones as selective cytotoxic agents through rigidifying the molecular scaffold and precisely tuning the functional group positioning.