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.

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.

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.

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.

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.

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.

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.

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.

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 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.

Estrogen receptor alpha (ERα) is the defining therapeutic target in hormone receptor-positive breast cancer, yet acquired resistance remains a persistent barrier to durable clinical benefit. Patent application WO 2026/039467 A1 discloses small molecules that activate an anticipatory unfolded protein response (a-UPR) through ERα, converting receptor engagement into selective cytotoxic stress. This mechanism diverges fundamentally from classical antagonism or degradation and demonstrates preferential activity in ERα-positive tumor modelsoffering a conceptually distinct strategy for overcoming endocrine resistance.

Antibody-drug conjugates (ADCs) consist of a cytotoxin covalently linked to a target-specific antibody. ADCs are designed to release the cytotoxic drug upon internalization by cells expressing the select antigen. However, the true potential of an ADC becomes diminished by several factors, including high hydrophobicity of the biologic, which results in either aggregation in vitro or poor pharmacokinetics in vivo, thereby curtailing its efficacy. Hence, one of the goals in designing next generation ADCs is creating hydrophilic linker-payloads to overcome these challenges. Here, we describe generation and characterization of cathepsin and glucuronidase-cleavable linkers attached to a novel, short, stable, hydrophilic 1-amino-β-d-glucuronic acid spacer. These hydrophilic spacer-linkers, attached to the exatecan payload, were conjugated to the HER-2-targeting antibody trastuzumab to obtain ADCs with a drug-to-antibody ratio (DAR) of 8. The ADC with an amino-glucuronic acid spacer combined with a glucuronide linker (AV-L03) showed superior hydrophilicity compared to a cathepsin cleavable GGFG linker; both ADCs included the same hydrophilic short spacer and exatecan payload. The ADC with the hydrophilic AV-L03 linker-exatecan payload (AV-DL055) conjugated to trastuzumab displayed potent in vitro cytotoxicity, improved plasma stability, and remarkable in vivo efficacy in a mouse xenograft model compared to an ADC comprising trastuzumab conjugated to DXd payload via a tetrapeptide (hydrophobic GGFG) linker.

Three series of 5-fluoro-2'-deoxyuridine (FdU) nucleotide analogues were studied as potential antiglioma pronucleotides. The 5'-OH position was esterified with H-phosphonate, phosphate, and acylphosphate residues, all of which had negative charges. Additionally, some carried protecting groups of varying lipophilicity at the 3'-OH position. The acylphosphate moiety also contained different hydrocarbon substituents. The amphiphilic nature of these compounds should render them water-soluble and facilitate their permeation through the cell membranes. Inside the cell, they were expected to be converted to 5-fluoro-2'-deoxyuridine 5'-phosphate, a highly effective inhibitor of thymidylate synthetase. Two of the studied new FdU derivatives exhibited promising antiproliferative activity against the glioblastoma multiforme T98G cell line, an order of magnitude better than that of the parent nucleoside.

Diabetes is the most prevalent metabolic disorder distinguished by increased blood glucose levels. Unfortunately, none of the marketed treatments can cure the ailment. Glucokinase has recently emerged as a novel target acting in both the liver and the pancreas. The activity of this novel protein in the liver is regulated by a protein called glucokinase regulatory protein (GKRP). The study aimed to identify novel GKRP modulators and evaluate their potential as antidiabetic agents using a comprehensive approach incorporating in silico, in vitro, and in vivo methods. In the quest for novel GKRP modulators, pharmacophore models were developed using Hypogen and HipHop methodologies. The optimal pharmacophore hypothesis, featuring 1HBA, 1HY, 1HBD, and 1RA, demonstrated a root mean-square deviation of 0.88 Å and a high correlation coefficient of 0.88. Fisher's randomization and Cat Scramble tests confirmed the statistical validity of the models, with a 95% confidence level. The validated pharmacophore model was employed in a virtual screening of the NCI database, resulting in the retrieval of key hits, including NCS 1972 and NCS 80683. These compounds were subjected to docking studies and in vitro enzyme-based GKRP modulatory assay, revealing favorable binding interactions with the GKRP active site and IC50 of 1.60 and 3.04 nM, respectively. In vivo evaluations showed that NCS 1972 (2.5 mg/kg) significantly improved lipid profiles, reduced liver hypertrophy and adiposity, and enhanced body mass index, 0.27 ± 0.02 g/mm, 0.21 ± 0.12g/mm, 0.70 ± 2.82 g/cm2 respectively, compared to the HFD-STZ group. Histopathological analyses demonstrated substantial cellular restoration in pancreatic and liver tissues, with NCS 1972 exhibiting superior efficacy over NCS 80683. Additionally, gene expression studies revealed that both compounds corrected HFD-STZ-induced dysregulation of glucose metabolism and inflammatory markers. These findings underscore the significant therapeutic potential of NCS 1972 in mitigating diabetes, suggesting its promise as a novel antidiabetic agent.

Advances in computational design have greatly accelerated antimicrobial peptide engineering. In this study, three Plasmodium chabaudi-derived peptides (PcDBS1R1, PcDBS1R5, and PcDBS1R9), generated using the Joker computational design algorithm, were synthesized and characterized for their structural and functional properties. Biophysical analyses revealed that PcDBS1R5 and PcDBS1R9 predominantly adopted α-helical structures with high amphipathicity, whereas PcDBS1R1 exhibited greater structural plasticity. PcDBS1R5 and PcDBS1R9 displayed antibacterial activity against an Acinetobacter baumannii clinical isolate, whereas PcDBS1R1 showed pronounced antibiofilm effects. None of the peptides exhibited cytotoxicity toward murine macrophages, and all significantly reduced nitric oxide production in lipopolysaccharide-stimulated macrophages, suggesting potential anti-inflammatory activity. Overall, these findings demonstrate that computer-aided design of P. chabaudi-derived peptides can yield molecules with antibiofilm, and immunomodulatory properties, minimal cytotoxicity, and promising therapeutic potential as scaffolds for next-generation peptide-based treatments targeting biofilm-associated bacterial infections.

Chronic hepatitis B virus (HBV) infection remains a significant global health challenge, yet current available treatment options are still limited. Roche first reported the efficacy of a class of xanthone derivatives in diminishing covalently closed circular DNA (cccDNA) levels; however, their coplanarity constrained their drug-likeness. We introduced more flexible and hydrophilic side chains to xanthones, yielding a series of compounds with enhanced antiviral activity and better pharmacokinetic (PK) profiles. The representative compound 35 outperformed Rf.59 with respect to both antiviral activity (0.1 μM vs 0.68 μM) and PK properties, including a longer half-life (2.54 h vs 1.48 h), a 2-fold higher AUC0-∞ (1571 vs 783 ng·h/mL), and improved oral bioavailability (43.7% vs 36.4%).

Provided herein are novel 3-heteroaryl pyrrolidine and piperidine 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.

Photo-immunotherapy combines phototherapy and immunotherapy, which can eliminate primary tumors and induce host immunity to control distant metastases. However, the effectiveness may be attenuated by the tumor defense mechanisms associated with glutamine metabolism regulation. In this work, a self-assembled stimulator was prepared for glutamine-starvation-potentiated photo-immunotherapy, which is composed of telaglenastat as the glutaminase inhibitor, chlorin e6 (Ce6) as the photosensitizer, and interferon stimulatory DNA (ISD). Ce6 transfers energy from light to molecular oxygen, generating reactive oxygen species (ROS). Telaglenastat assists in the downregulation of endogenous glutathione. Thus, ROS neutralization can be prevented, and the photodynamic therapy effect is enhanced. Additionally, the cGAS-STING signaling pathway activated by ISD remodels the tumor microenvironment by polarizing M2-type tumor-associated macrophages into M1, which finally enhances immunogenic cell death. The prepared nanomedicine combines glutamine starvation and a photo-immunotherapy strategy, offering new insights into cancer treatment.

We report the total synthesis of sulfobacin A (1) and its stereoisomeric analogue 1a via dynamic kinetic resolution of racemic precursors using catalytic asymmetric reactions to establish three stereogenic centers without chiral building blocks. Late-stage optimization of the amide coupling improved the overall yield of 1 to 7.8%. Preliminary biological evaluation reveals that sulfobacin A is recognized by multiple T-cell subsets (CD4, CD8, and NKT cells) when presented by multiple CD1 tetramers, indicating that this sulfonolipid can engage T cells that influence both innate (NKT) and adaptive (CD4 and CD8) immune responses. Moreover, our data suggest that modification of the lipid headgroup or alteration to a monoacyl lipid diminishes CD1-mediated T-cell recognition.