ACS Med Chem Lett
· 2026 Jun · PMID 42305199
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Targeted protein degradation and rational combination therapy redefine cancer treatment by addressing both immune suppression and tumor-intrinsic signaling. Bifunctional degraders eliminate key regulatory kinases, while...Targeted protein degradation and rational combination therapy redefine cancer treatment by addressing both immune suppression and tumor-intrinsic signaling. Bifunctional degraders eliminate key regulatory kinases, while dual-pathway inhibition suppresses compensatory survival mechanisms. These complementary approaches illustrate a shift toward coordinated therapeutic control, enabling more durable antitumor responses through simultaneous modulation of immune activation and oncogenic pathways.
Qian S, Qiu H, Sanchez PR
… +5 more, Head SA, Hartke R, Liu JO, Zheng W, Jin Z
ACS Med Chem Lett
· 2026 Jun · PMID 42305198
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Inspired by the anticancer marine natural product superstolide A, we previously designed and synthesized a truncated analogue, designated ZJ-101, that retains the potent anticancer activity of the original natural produc...Inspired by the anticancer marine natural product superstolide A, we previously designed and synthesized a truncated analogue, designated ZJ-101, that retains the potent anticancer activity of the original natural product. In this study, using ZJ-101 as a lead compound, we conducted molecular design, convergent synthesis, and structure-activity optimization, resulting in the discovery of new analogues exhibiting anticancer activity approximately 30-80-fold more potent than ZJ-101, with IC values predominantly in the single-digit nanomolar range.
Stary D, El-Kasaby A, Boytsov D
… +9 more, Zaręba P, Godyń J, Maszczyk M, Rzepka Z, Wrześniok D, Sotriffer C, Sandtner W, Freissmuth M, Bajda M
ACS Med Chem Lett
· 2026 Jun · PMID 42305197
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Creatine transporter 1 (CT1, SLC6A8) regulates cellular energy levels. Mutations in CT1 cause severe neurological disorders, whereas CT1 overexpression has been associated with cancer progression. Rational development of...Creatine transporter 1 (CT1, SLC6A8) regulates cellular energy levels. Mutations in CT1 cause severe neurological disorders, whereas CT1 overexpression has been associated with cancer progression. Rational development of CT1 inhibitors has been limited by the absence of structural data. Here, we constructed homology models of CT1 representing distinct transport states and integrated them into a structure-based virtual screening workflow. From this approach, 16 top-ranked compounds were tested . Among them, compound showed inhibitory activity with an IC comparable to the reference ligand ompenaclid. We demonstrate that tiagabine () and its analogue also inhibit CT1. Following the completion of this study, cryo-EM structures of CT1 were reported. Retrospective comparison confirmed good agreement between our models and the experimental structures. These findings provide a computational-experimental framework for CT1 inhibitor discovery and support future structure-based drug design.
Ripa L, Cassani C, Hughes G
… +17 more, Ranieri B, Ullah V, Zambelloni R, Andreasson T, Collins M, Lindberg B, Llinas A, Pehrson R, Barylyuk K, Johansson J, Ek M, Gunnarsson A, Jung B, Lundqvist S, Novén A, Sandmark J, Åstrand A
ACS Med Chem Lett
· 2026 Jun · PMID 42305196
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Histone deacetylase 6 (HDAC6) is a cytosolic enzyme that regulates protein acetylation and contributes to the pathogenesis of various lung diseases. We report the discovery and characterization of a novel HDAC6 degrader,...Histone deacetylase 6 (HDAC6) is a cytosolic enzyme that regulates protein acetylation and contributes to the pathogenesis of various lung diseases. We report the discovery and characterization of a novel HDAC6 degrader, compound , designed by conjugating a selective hydroxamic acid HDAC6 inhibitor () to a cereblon-recruiting ligand via a short, rigid linker. Compound exhibited selective HDAC6 degradation with subnanomolar degradation potency in bronchial epithelium cells, effectively inducing α-tubulin hyperacetylation without affecting histone-3 acetylation. In mice, subcutaneous administration achieved high bioavailability (65%) and sustained HDAC6 knockdown in lung tissue for up to 96 h after a single dose, repeated dosing further enhanced degradation and α-tubulin acetylation. Safety and secondary pharmacology profiling confirmed a favorable preclinical safety and selectivity profile. These findings established compound as a potent, selective HDAC6 degrader suitable as a starting point and tool for studying HDAC6-related diseases in the lung epithelium and beyond.
ACS Med Chem Lett
· 2026 Jun · PMID 42305195
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Targeted protein degradation and metabolic inhibition represent complementary strategies in oncology. TEAD-directed PROTACs enable catalytic degradation of transcription factors that drive Hippo pathway dysregulation, wh...Targeted protein degradation and metabolic inhibition represent complementary strategies in oncology. TEAD-directed PROTACs enable catalytic degradation of transcription factors that drive Hippo pathway dysregulation, while NAT8L inhibitors disrupt N-acetylaspartate metabolism in acute myeloid leukemia. These approaches address undruggable targets and chemoresistance and demonstrate potential synergy with existing therapies, highlighting emerging paradigms in precision cancer treatment.
Magniez A, Giovannini J, Zipfel P
… +7 more, Rémondin C, Saïdoun H, Davis A, Rivera S, Dallemagne P, Rochais C, Lepailleur A
ACS Med Chem Lett
· 2026 Jun · PMID 42305194
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Membrane type 5-matrix metalloproteinase (MT5-MMP, MMP-24), an η-secretase involved in amyloid precursor protein processing, is a promising but unexplored target in Alzheimer's disease. We report here the identification...Membrane type 5-matrix metalloproteinase (MT5-MMP, MMP-24), an η-secretase involved in amyloid precursor protein processing, is a promising but unexplored target in Alzheimer's disease. We report here the identification of a first nonpeptidic hit for MT5-MMP through a structure-guided approach. A homology model of the MT5-MMP catalytic domain was built from the MT3-MMP/batimastat structure and validated by both docking and experimental inhibition data obtained with batimastat (IC = 3 nM). To account for binding-site plasticity, especially that of the S1' pocket, molecular dynamics and ensemble docking were applied to a zinc-binding group (ZBG)-focused library of 3851 compounds. Although the initial screening campaign yielded only weakly active candidates, analysis of docking poses identified a relevant scaffold for optimization. Replacement of a carboxylic acid ZBG by a hydroxamic acid led to compound , which inhibited MT5-MMP with an IC of 6 μM and established a first nonpeptidic hit for future optimization.
Liang J, Lambrecht MJ, Huestis MP
… +33 more, Zhu B, Barton LM, Castanedo GM, Ung PM, Larouche-Gauthier R, Jakalian A, Leclerc JP, Yadav A, Haghshenas P, Aubert-Nicol S, Ismaili H, Zhao L, Leblanc M, de Almeida H, Wang Q, Garner T, Tan S, Prangley MS, Pang J, Murray JM, Yu C, Hsu PL, Rutz S, Ishizuka I, Huang H, Gao C, Chen M, Mutter-Rottmayer L, Kakiuchi-Kiyota S, Leung DH, Kou P, Bao L, Wang X
ACS Med Chem Lett
· 2026 Jun · PMID 42305193
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In the preceding work in this issue (10.1021/acsmedchemlett.6c00103), we described our initial structure-activity relationship (SAR) optimization that led to a pan-Cbl inhibitor () that demonstrated efficacy in a mouse C...In the preceding work in this issue (10.1021/acsmedchemlett.6c00103), we described our initial structure-activity relationship (SAR) optimization that led to a pan-Cbl inhibitor () that demonstrated efficacy in a mouse CT26 syngeneic model. Unfortunately, attempts to improve TGI with higher doses of resulted in poor tolerability which we attributed to a lack of selectivity between Cbl-b and c-Cbl (∼2× by surface plasmon resonance (SPR)). Herein, we report our continued efforts that led to a breakthrough in achieving Cbl-b selectivity (up to 37×). The lead compound demonstrated 14× selectivity against c-Cbl by SPR, was potent in a PBMC cell assay, and showed good oral exposure in mice. When tested in a CT26 model, displayed improved tumor growth inhibition compared to our previously reported pan-Cbl inhibitor (TGI 145% vs 82%). More importantly, was better tolerated than , supporting our hypothesis that a selective Cbl-b inhibitor could be advantageous relative to a pan-Cbl inhibitor.
Alegbejo Price TO, Silva DG, Vaidergorn MM
… +9 more, Augusto BS, Matheeussen A, Van Pelt N, Caljon G, Riley J, Read KD, Medina-Franco JL, Nonato MC, Emery FS
ACS Med Chem Lett
· 2026 Jun · PMID 42305192
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Neglected tropical diseases such as Chagas disease remain poorly served by current chemotherapies due to toxicity and the emergence of drug resistance. Nitroaromatic compounds represent an established antitrypanosomal st...Neglected tropical diseases such as Chagas disease remain poorly served by current chemotherapies due to toxicity and the emergence of drug resistance. Nitroaromatic compounds represent an established antitrypanosomal strategy, relying on bioactivation by type I nitroreductases. In this study, a fragment-based design approach was applied to the nitroaromatic drugs nifurtimox and benznidazole to generate a novel hybrid scaffold, ()--benzyl-2-((5-nitrofuran-2-yl)-methylene)-hydrazine-1-carboxamide (). A series of twenty-two analogues was synthesized by modifying the benzylamine substituent and evaluated for antitrypanosomal activity and susceptibility to nitroreductase I-mediated activation and early ADME properties. Among the series, ()--(4-methylbenzyl)-2-((5-nitrofuran-2-yl)-methylene)-hydrazine-1-carboxamide () and () exhibited potent anti- activity (0.14 μM and 0.23 μM), anti- activity (0.59 ± 0.03 μM and 29.3 ± 15.6 μM), and anti- (0.87 ± 0.8 μM and 7.44 ± 1.00 μM) in parasite cultures. These findings identify this chemotype as a promising starting point for the further development of nitroreductase-activated therapeutics for Trypanosomiasis disease.
ACS Med Chem Lett
· 2026 Jun · PMID 42305191
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As ligand molecular weight increases, strategic structural optimization becomes increasingly important because larger ligands contain more modifiable atoms, making comprehensive exploration impractical. We present the st...As ligand molecular weight increases, strategic structural optimization becomes increasingly important because larger ligands contain more modifiable atoms, making comprehensive exploration impractical. We present the structure-activity relationship (SAR) analysis of LUNA18 (paluratide, an 11-mer macrocyclic peptide RAS inhibitor) focusing on the amino acid side chains at position 5 in the solvent-exposed region. The analysis revealed that the contribution of position 5 to inhibitory activity depends on its local environment. Structural analysis identified two structural features: peptides forming a ″cavity″, which possess the hydrophobic interaction network among positions 1, 8, and 9, exhibited minimal changes upon position 5 modification, whereas those forming a ″groove″, lacking this interaction network, showed significant differences. These findings provide practical guidelines for optimizing macrocyclic peptides: evaluate the contributions of solvent-exposed side chain at key points and interpret SARs in the context of spatially proximal side chains.
Sedlacek Miskerikova M, Houfkova A, Benkova M
… +5 more, Andrys R, Janousek J, Soukup O, Musilek K, Benek O
ACS Med Chem Lett
· 2026 Jun · PMID 42305190
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17β-hydroxysteroid dehydrogenase type 10 (17β-HSD10) is a multifunctional mitochondrial enzyme and a potential drug target for the treatment of various pathologies, including Alzheimer's disease (AD). In this study, five...17β-hydroxysteroid dehydrogenase type 10 (17β-HSD10) is a multifunctional mitochondrial enzyme and a potential drug target for the treatment of various pathologies, including Alzheimer's disease (AD). In this study, five new benzothiazole-derived 17β-HSD10 inhibitors were developed based on structure-activity relationship (SAR) analyses of previously published compounds. To evaluate the inhibitory effects, cytotoxicity, and therapeutic potential of these new compounds, several enzyme- and cell-based methods were employed. All prepared compounds exhibited high inhibitory potential and confirmed good biomembrane permeation. Three inhibitors (, , and ) showed lower IC values in both enzyme- and cell-based assays than the formerly published hit compounds. The compounds were also found to reduce the pathological effects associated with 17β-HSD10 overexpression, although not the combined pathological effects of 17β-HSD10 overexpression within an amyloid-β rich environment.
ACS Med Chem Lett
· 2026 May · PMID 42157852
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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 st...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.
Guo L, Chen X, Liu X
… +4 more, Liu N, Sun K, Hong H, Zhao D
ACS Med Chem Lett
· 2026 May · PMID 42157851
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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...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 outperformed 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 AUC (1571 vs 783 ng·h/mL), and improved oral bioavailability (43.7% vs 36.4%).
ACS Med Chem Lett
· 2026 May · PMID 42157850
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Schistosomiasis is a parasitic disease that affects millions of people but has only one treatment option (praziquantel) available. There is concern about the emergence of praziquantel-resistant schistosomes and the need...Schistosomiasis is a parasitic disease that affects millions of people but has only one treatment option (praziquantel) available. There is concern about the emergence of praziquantel-resistant schistosomes and the need for the development of new molecules to complement and/or act as an alternative to praziquantel. Prenylated quinolones are natural products generally produced by bacteria, wherein they are used as quorum-sensing molecules. Inspired by nature, we have synthesized 37 mimetics of these naturally produced molecules and established their antischistosomal activity against schistosomula and adult worms. Several hits with low micromolar (<3 μM) activity against both schistosomula and adult worms were identified. These hits are fast-acting, demonstrating greater than 50% inhibition of adult worms within 4 h at a concentration of 10 μM. Among them, , a diprenylated quinolone, showed moderate activity, achieving 48% worm burden reduction at 200 mg/kg.
Jammalamadaka V, Liu J, Bhakta S
… +4 more, Velupula S, Martha B, Jonnalagadda V, Junutula JR
ACS Med Chem Lett
· 2026 May · PMID 42157849
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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...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.
ACS Med Chem Lett
· 2026 May · PMID 42157848
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DNA-encoded library (DEL) technology has emerged as a transformative platform for the discovery of bioactive small molecules against challenging therapeutic targets including G protein-coupled receptors (GPCRs). As a cli...DNA-encoded library (DEL) technology has emerged as a transformative platform for the discovery of bioactive small molecules against challenging therapeutic targets including G protein-coupled receptors (GPCRs). As a clinically pivotal class of membrane-bound targets, GPCRs pose inherent challenges in the discovery of novel ligands. This Microperspective highlights recent methodological advances (2015-2026) that enable DEL selections against GPCRs, thereby facilitating the identification of diverse ligand modalities, including agonists, antagonists, allosteric modulators, and biased ligands. Furthermore, we discuss current challenges and future directions in the application of DEL technology to GPCR drug discovery, with a specific emphasis on opportunities in receptor stabilization, selection strategy design, and computational method development.
Elhalawaty EA, Alseedy HA, Woodland JG
… +8 more, Wicht KJ, Swart T, Rangel GW, Hoppe HC, Chibale K, Llinás M, Abadi AH, Ahmed NS
ACS Med Chem Lett
· 2026 May · PMID 42157847
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Analogues of tadalafil, an FDA-approved inhibitor of human phosphodiesterase 5, have been reported to block the growth of human . Herein, we synthesized and evaluated 56 tadalafil analogues prepared as pure diastereomers...Analogues of tadalafil, an FDA-approved inhibitor of human phosphodiesterase 5, have been reported to block the growth of human . 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 . Compound was the most potent analogue, with an IC of 80 nM against cultured parasites and an IC > 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 IspD (2-C-methyl-d-erythritol 4-phosphate cytidylyltransferase); it is possible that compounds and act by disrupting hemozoin formation whereas none of the tested analogues acted as IspD 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.
ACS Med Chem Lett
· 2026 May · PMID 42157846
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The invention in this patent application relates to Substituted Pyridine and Phenyl derivatives represented herein by Formula 1. These compounds are inhibitors of SLC6A19 (B0AT1) and may be useful as therapeutic and/or p...The invention in this patent application relates to Substituted Pyridine and Phenyl derivatives represented herein by Formula 1. These compounds are inhibitors of SLC6A19 (B0AT1) and may be useful as therapeutic and/or preventative agents to treat diseases or disorders associated with abnormal amino acid metabolism, abnormal amino acid transport, and/or abnormal amino acid level such as cardiovascular disorders, renal disorders, or metabolic diseases (for example phenylketonuria, NASH, NAFLD, heart failure, chronic kidney disease, and related disorders).
Bouton J, Bretteville A, Tresadern G
… +16 more, Shaffer P, Austin N, Buijnsters P, Cedervall EP, Darville N, Fonteyn I, Leenaerts J, Lamenca CM, Mertens L, Peeters D, Velter AI, Roosbroeck YV, Ebneth A, Bartolomé JM, Trabanco AA, Oehlrich D
ACS Med Chem Lett
· 2026 May · PMID 42157845
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Alzheimer's disease (AD) is a neurodegenerative disorder characterized by extracellular amyloid-β plaque accumulation and intracellular tau neurofibrillary tangles, with tau pathology correlating more closely with cognit...Alzheimer's disease (AD) is a neurodegenerative disorder characterized by extracellular amyloid-β plaque accumulation and intracellular tau neurofibrillary tangles, with tau pathology correlating more closely with cognitive decline. Modulation of tau phosphorylation through the regulation of O-GlcNAcylation, a post-translational modification controlled by O-GlcNAcase (OGA), represents a promising therapeutic strategy. In this study, we report the optimization of a pyrimidine hit identified by high-throughput screening, leading to the discovery and optimization of a novel series of 5-azaindole-based OGA inhibitors. From this series, compound was identified as an tool candidate that demonstrated a favorable pharmacokinetic profile and measurable brain exposure. Pharmacodynamic studies in murine models demonstrated that compound induced a significant and transient elevation of brain O-GlcNAcylation levels, confirming the target engagement. These findings underscore the potential of 5-azaindole-based OGA inhibitors as a novel validated chemotype for modulation of O-GlcNAcylation.
ACS Med Chem Lett
· 2026 May · PMID 42157844
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This patent describes compounds and pharmaceutical compositions thereof for inhibiting PDE4 and treatment of disease.This patent describes compounds and pharmaceutical compositions thereof for inhibiting PDE4 and treatment of disease.
ACS Med Chem Lett
· 2026 May · PMID 42157843
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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,...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.