ACS Med Chem Lett
· 2026 Feb · PMID 41704392
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Provided herein are novel cyclopentapyrrole compounds as orexin receptor agonists, pharmaceutical compositions, use of such compounds in treating sleep disorders, namely, narcolepsy and hypersomnia, and processes for pre...Provided herein are novel cyclopentapyrrole 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.
Pandey K, Slater O, Jeschke GE
… +3 more, Kontoyianni M, Plunkett KN, Fisher DJ
ACS Med Chem Lett
· 2026 Feb · PMID 41704391
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A structure-based designed library of new 5,5'-methylenedisalicylic acid (MDSA) derivatives were synthesized as a functional core and explored for their antibacterial activity against . Various well-established reactions...A structure-based designed library of new 5,5'-methylenedisalicylic acid (MDSA) derivatives were synthesized as a functional core and explored for their antibacterial activity against . Various well-established reactions such as amide coupling, basic ester hydrolysis, phosphorylation, sulfonation, acetylation, and hydrogenation reactions were utilized to tune or substitute the carboxylic acid and phenolic groups of MDSA, converting them into amide, ester, phosphoryl, sulfonyl, and acetyl functionalities. Both symmetrical and asymmetrical derivatives were prepared and subsequently tested for mammalian cell cytotoxicity, CppA enzyme inhibition, and the inhibition of infection. Among these, compounds , , and were identified as the most potent and biologically active inhibitors. Additionally, the docking results against the newly constructed CppA model revealed that MDSA and compounds - form interactions with different residues such as G42, R166, N167, and R237, supporting the requirement of these interactions for biological activity.
ACS Med Chem Lett
· 2026 Feb · PMID 41704390
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Complete estrogen receptor antagonists (CERANs) are effective against advanced estrogen receptor-positive (ER+) breast cancers, but current chemical scaffolds limit our ability to explore the full range of ER pharmacolog...Complete estrogen receptor antagonists (CERANs) are effective against advanced estrogen receptor-positive (ER+) breast cancers, but current chemical scaffolds limit our ability to explore the full range of ER pharmacology. We report the synthesis of OP-1690 (), a CERAN featuring a distinct unconstrained core. Structural and biophysical studies reveal that uniquely promotes estrogen receptor alpha (ERα) ligand binding domain (LBD) tetramer formation, which goes beyond the conventional homodimer. This study shows how new CERAN scaffolds can reveal unrecognized mechanisms of action.
ACS Med Chem Lett
· 2026 Feb · PMID 41704389
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Two recent patent applications illustrate how psychedelic drug development is expanding beyond molecules and experiences toward deployable therapeutic systems. One focuses on solid-state optimization of a lysergamide ana...Two recent patent applications illustrate how psychedelic drug development is expanding beyond molecules and experiences toward deployable therapeutic systems. One focuses on solid-state optimization of a lysergamide analogue to ensure manufacturability and stability, while the other applies machine-learning-driven neurophysiological biomarkers to predict patient response. Together, they address complementary translational bottlenecks in psychedelic medicine.
Ferrandi G, Bagnolini G, Poppi L
… +11 more, Masi M, Previtali V, Andonaia A, Varignani G, Veronesi M, De Franco F, Falchi F, Di Stefano G, Girotto S, Roberti M, Cavalli A
ACS Med Chem Lett
· 2026 Feb · PMID 41704388
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Synthetic lethality has proven to be a tactical paradigm to design synergistic anticancer drug combinations. In this context, we leveraged BRCA2 and PARP as a synthetic lethal target pair to consolidate the use of small...Synthetic lethality has proven to be a tactical paradigm to design synergistic anticancer drug combinations. In this context, we leveraged BRCA2 and PARP as a synthetic lethal target pair to consolidate the use of small molecule inhibitors of RAD51-BRCA2 protein-protein interaction as inducers of the BRCAness phenotype that sensitizes -functional cancer cells to PARP inhibitors. Starting from compound , a phenyl furan-carboxyquinoline, we developed a series of analogues, leading to derivative . This compound effectively inhibits RAD51-BRCA2 interaction, impairs homologous recombination, and synergizes with olaparib in BxPC-3 pancreatic cancer cells, inducing synthetic lethality in both 2D and 3D spheroids. Additionally, showed efficacy in human pancreatic cancer cells and no toxicity in normal pancreatic cells, positioning it as an early tool compound and a starting point for further optimization.
ACS Med Chem Lett
· 2026 Feb · PMID 41704387
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Provided herein are novel compounds as glucagon-like peptide-1 receptor agonists, pharmaceutical compositions, use of such compounds in treating diabetes, and processes for preparing such compounds.Provided herein are novel compounds as glucagon-like peptide-1 receptor agonists, pharmaceutical compositions, use of such compounds in treating diabetes, and processes for preparing such compounds.
ACS Med Chem Lett
· 2026 Feb · PMID 41704386
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Provided herein are novel substituted pyrazolo-pyrimidine compounds as PIKfyve inhibitors, pharmaceutical compositions, use of such compounds in treating neurological diseases, and processes for preparing such compounds.Provided herein are novel substituted pyrazolo-pyrimidine compounds as PIKfyve inhibitors, pharmaceutical compositions, use of such compounds in treating neurological diseases, and processes for preparing such compounds.
ACS Med Chem Lett
· 2026 Feb · PMID 41704385
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Recent patent disclosures highlight complementary strategies to modulate transcriptional and cell-cycle control in cancer. Selective and dual p300/CBP degraders introduce emerging epigenetic degradation modalities, while...Recent patent disclosures highlight complementary strategies to modulate transcriptional and cell-cycle control in cancer. Selective and dual p300/CBP degraders introduce emerging epigenetic degradation modalities, while biomarker-guided CDK4 inhibition and a crystalline CDK2 inhibitor exemplify precision oncology and potential late-stage development. Together, these inventions illustrate how mechanistic innovation, patient stratification, and pharmaceutical execution converge to advance targeted anticancer therapies.
ACS Med Chem Lett
· 2026 Feb · PMID 41704384
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Despite advancements in hit-finding technologies, many drug targets are considered difficult-to-drug (D2D) or difficult-to-ligand (D2L). Here, we present an analysis of 21 hit-finding campaigns across three research orga...Despite advancements in hit-finding technologies, many drug targets are considered difficult-to-drug (D2D) or difficult-to-ligand (D2L). Here, we present an analysis of 21 hit-finding campaigns across three research organizations within the Roche group, focusing on D2D and D2L targets. DNA-encoded library technology (DELT) was the most successful method in providing validated hits and lead series. High-throughput, covalent, and peptide screens also yielded progressable chemical matter in a substantial number of cases. In contrast, fragment and virtual screens, while effective in generating validated hits, demonstrated lower success rates. Stratifying targets into D2D and D2L categories provided a useful framework for estimating the likelihood of project success and informing additional screening strategies, with D2D targets showing higher rates of chemical enablement. Our findings indicate DELT as a valuable experimental tool for assessing ligandability and highlight the importance of informed integrated hit discovery by tailoring hit-finding strategies to target characteristics.
Lysenko V, Theriault ME, Sterk FAC
… +4 more, Choudhari P, Son S, Lewis K, Martin NI
ACS Med Chem Lett
· 2026 Feb · PMID 41704383
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The escalating threat of antibacterial resistance is a pressing global issue that highlights the urgent need for innovative antibiotics. In this regard, the recent discovery of evybactina nonribosomal depsipeptide antib...The escalating threat of antibacterial resistance is a pressing global issue that highlights the urgent need for innovative antibiotics. In this regard, the recent discovery of evybactina nonribosomal depsipeptide antibiotic that selectively and effectively inhibits the growth of is notable given its unique structure and mechanism of action. In a previous report, we described the first total synthesis of evybactin and a revision of the originally assigned structure. Building on this, we report here a series of structure-activity relationship studies with evybactin. In doing so, we synthesized a total of 21 novel evybactin analogues by performing an alanine scan and exploring multiple modifications, including variations of the ester-linked macrocycle, substitution of the formylated N-terminus, and removal of positively charged side chains. Our results provide valuable insights into the significance of certain amino acids and other structural features that underscore the potent antitubercular activity of this unique natural product.
ACS Med Chem Lett
· 2026 Feb · PMID 41704382
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Fentanyl is a benchmark μ-opioid analgesic but is constrained by respiratory risk. Searching for new entities with reduced respiratory liability, pharmacophore portability was probed by replacing the piperidine moiety wi...Fentanyl is a benchmark μ-opioid analgesic but is constrained by respiratory risk. Searching for new entities with reduced respiratory liability, pharmacophore portability was probed by replacing the piperidine moiety with 2-azaspiro[3.3]-heptane while preserving phenethyl/anilide geometry. This spiro analogue retained fentanyl-class behaviorμ-opioid receptor (MOR)-preferred binding (MOR > κ-opioid receptor (KOR) ≫ δ-opioid receptor (DOR)), absent β-arrestin-2 recruitment, and full hot-plate/tail-flick antinociceptiondespite ∼10-fold right-shift in potency versus fentanyl. In mice, it was stable and short-acting with a serum half-life of ∼27 min after an intravenous bolus dose. Whole-body plethysmography showed rapid, dose-dependent depression of respiration that was evident only at high doses. In sum, these studies present a topology-level core swap; preserving the fentanyl signature while decoupling potency from exposure, mapping the pharmacophore's boundary conditions and providing an actionable, spiro-enabled blueprint to tune MOR signaling and dispositionand recover affinity via structure-activity relationship (SAR)for next-generation opioid leads.
Davies LJ, Whitefield C, Kim H
… +3 more, Nitsche C, Jackson CJ, Frkic RL
ACS Med Chem Lett
· 2026 Feb · PMID 41704381
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Heparanase is the sole enzyme responsible for breaking down heparan sulfate within the extracellular matrix, and its overexpression is linked to human diseases. Despite heparanase being a promising drug target, most effo...Heparanase is the sole enzyme responsible for breaking down heparan sulfate within the extracellular matrix, and its overexpression is linked to human diseases. Despite heparanase being a promising drug target, most efforts have focused on substrate mimetics, which have failed clinical trials, highlighting the need for new inhibitor scaffolds. Here, we employed fragment-based drug design to explore a novel chemical space to develop small molecule inhibitors of heparanase. We used a crystallographic and computational approach to identify 31 fragments that bind heparanase; five of these inhibited heparanase in the micromolar range. One of these fragments underwent two cycles of fragment growing, which resulted in a compound with a 7-fold increased potency compared to the initial hit. The results from our fragment screen unveil untapped chemical space for heparanase inhibition, paving the way for the development of potent drug leads with the potential to transform the treatment of heparanase-related diseases.
ACS Med Chem Lett
· 2026 Feb · PMID 41704380
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Provided herein are novel compounds as ARNT degraders, pharmaceutical compositions, use of such compounds in treating cancer, in particular, hematological cancer, and processes for preparing such compounds.Provided herein are novel compounds as ARNT degraders, pharmaceutical compositions, use of such compounds in treating cancer, in particular, hematological cancer, and processes for preparing such compounds.
ACS Med Chem Lett
· 2026 Feb · PMID 41704379
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Poly-(ADP-ribose) polymerase 1 (PARP1) is the most abundant and well-characterized member of PARP family and plays a significant role in DNA damage detection and repair. Cancer cells with homogeneous recombination defici...Poly-(ADP-ribose) polymerase 1 (PARP1) is the most abundant and well-characterized member of PARP family and plays a significant role in DNA damage detection and repair. Cancer cells with homogeneous recombination deficiency (HRD) depend on PARP1 mediated DNA repair for survival, which makes PARP1 as a potential cancer treatment target. This patent highlights the synthesis and pharmaceutical composition of novel quinazolinone based PARP inhibitors for cancer treatment.
ACS Med Chem Lett
· 2026 Feb · PMID 41704378
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Provided herein are novel 6-aminopurine derivatives as POLQ inhibitors, pharmaceutical compositions, use of such compounds in treating cancer, and processes for preparing such compounds.Provided herein are novel 6-aminopurine derivatives as POLQ inhibitors, pharmaceutical compositions, use of such compounds in treating cancer, and processes for preparing such compounds.
ACS Med Chem Lett
· 2026 Feb · PMID 41704377
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Provided herein are novel compounds as PKC-theta inhibitors, pharmaceutical compositions, use of such compounds in treating autoimmune or inflammatory diseases, and processes for preparing such compounds.Provided herein are novel compounds as PKC-theta inhibitors, pharmaceutical compositions, use of such compounds in treating autoimmune or inflammatory diseases, and processes for preparing such compounds.
Zioła P, Malarz K, Pacholczyk M
… +4 more, Cieślik W, Rawicka P, Musioł R, Mrozek-Wilczkiewicz A
ACS Med Chem Lett
· 2026 Feb · PMID 41704376
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Styrylquinoline analogues exhibiting antiproliferative activity against glioblastoma multiforme were tested for tyrosine kinase inhibition. A preliminary structure activity relationship analysis based on previous results...Styrylquinoline analogues exhibiting antiproliferative activity against glioblastoma multiforme were tested for tyrosine kinase inhibition. A preliminary structure activity relationship analysis based on previous results showed that the styrylquinoline fragment is a promising privileged structure. The addition of appropriate pharmacophores to both the quinoline structure and the benzene ring, which was attached to the 2-position, significantly altered the antiproliferative properties. Namely, OH or NO substituents had a positive effect on activity, while F and OAc molecular fragments had a negative impact. Screening conducted on a panel of receptor tyrosine kinases revealed the high potential of the tested compounds for use as insulin-like growth factor 1 receptor inhibitors. Molecular docking performed on the insulin-like growth factor 1 receptor unphosphorylated inactive conformation supports screening results suggesting high binding affinity of the active styrylquinoline derivatives.
Arrigoni F, Ferrari A, Prpić H
… +5 more, Markeviciute E, Muzi A, Roscilli G, Gazzola S, Piarulli U
ACS Med Chem Lett
· 2026 Feb · PMID 41704375
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Negative crosstalk between α5β1 integrin and the p53-MDM2 regulatory axis contributes to glioblastoma progression and therapeutic resistance. To explore the potential of dual inhibition of these two biological targets, t...Negative crosstalk between α5β1 integrin and the p53-MDM2 regulatory axis contributes to glioblastoma progression and therapeutic resistance. To explore the potential of dual inhibition of these two biological targets, the dual targeting small molecule drug conjugate (SMDC) () was designed by coupling the MDM2 inhibitor SAR405838 to a selective α5β1 integrin ligand (phg-DGR-) () through a stable chemical linker. The resulting conjugate retained antiproliferative activity in U87-MG glioblastoma cells and induced p53 reactivation with minimal MDM2 induction. Cell cycle distribution analysis revealed a redistribution of cells from the G0/G1 phase to the G2/M phase exclusively upon treatment with conjugate , suggesting that a different mechanism of action is engaged. These findings support the potential of this dual-targeting approach through a dual-targeting SMDC as a promising therapeutic strategy against high-grade glioma overexpressing the α5β1 integrin receptor.
ACS Med Chem Lett
· 2026 Feb · PMID 41704374
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Cytochalasans are actin polymerization inhibitors with potent migrastatic activity, but their potential therapeutic use is limited by their cytotoxicity. Here, we describe a modular late-stage approach that introduces un...Cytochalasans are actin polymerization inhibitors with potent migrastatic activity, but their potential therapeutic use is limited by their cytotoxicity. Here, we describe a modular late-stage approach that introduces unprecedented 10-phenoxy substituents into the cytochalasan scaffold via a Mitsunobu reaction. A series of ten 10-phenoxycytochalasan analogues was synthesized and evaluated for actin polymerization inhibition, migrastatic activity, and cytotoxicity (BLM, MRC-5, and HaCaT). At 10 μM concentration, several 7-hydroxy-10-phenoxycytochalasans (-) significantly inhibited actin polymerization in vitro and showed migrastatic effects in a spheroid invasion assay. Para-substituents of the phenoxy group modulated cytotoxicity without compromising actin polymerization inhibition or migrastatic activity. In contrast, lipophilic ortho-substituents predicted by molecular docking to enhance actin binding failed to manifest migrastatic activity, underscoring the limitations of the molecular docking with this type of compounds. These findings demonstrate that migrastatic and cytotoxic effects can be decoupled in cytochalasan analogues and highlight 10-phenoxy substitution as a promising strategy toward noncytotoxic migrastatic agents.
Xu Z, Xiao Q, Liu Y
… +8 more, Jiang W, Liu L, Sun H, Yang X, Lu Z, Yan B, Long H, Zhang X
ACS Med Chem Lett
· 2026 Feb · PMID 41704373
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Werner syndrome helicase (WRN) has received significant interest due to its implication as a synthetic lethal target in microsatellite instability-high (MSI-H) cancers. Here we report the discovery of a novel allosteric...Werner syndrome helicase (WRN) has received significant interest due to its implication as a synthetic lethal target in microsatellite instability-high (MSI-H) cancers. Here we report the discovery of a novel allosteric covalent WRN inhibitor, compound , via structure-based medicinal design and pharmacokinetic optimization from VVD-214. Compound occupied a new cavity and formed an additional hydrogen bond with K894, thereby improving its activities. Compound exhibited high antiproliferation inhibitory activity against HCT116, an MSI-H colorectal cancer cell line. It also demonstrated favorable preclinical pharmacokinetic properties with superior plasma stability and exposure compared with VVD-214. Furthermore, compound showed statistically significant antitumor activity in the HCT116 xenograft mouse model with clear dose dependence.