Diamanti E, Alhayek A, Lacour A
… +9 more, Shahrour MW, Willocx D, Illarionov B, Fischer M, Stadler M, Reiling N, Herrmann J, Müller R, Hirsch AKH
ACS Med Chem Lett
· 2026 Apr · PMID 41982712
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To tackle the emerging resistance against existing antibiotics, we screened natural-product (NP) libraries against two underexploited target enzymes from the 2-methyl-d-erythritol 4-phosphate (MEP) pathway, namely, DXPS...To tackle the emerging resistance against existing antibiotics, we screened natural-product (NP) libraries against two underexploited target enzymes from the 2-methyl-d-erythritol 4-phosphate (MEP) pathway, namely, DXPS and IspD. We have chosen these two enzymes due to the availability of the crystal structures that helped to elucidate the putative binding modes of the NPs identified. The screening of a NP collection led to the discovery of myxobacteria-derived maracen A and Streptomyces-derived polyketomycin as the first NPs targeting these enzymes.
ACS Med Chem Lett
· 2026 Apr · PMID 41982711
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Provided herein are novel benzothiadiazine derivatives as Mas-related G protein-coupled receptor X2 (MRGPRX2) or MRGX2 (Mas-related Gene X2) antagonists, pharmaceutical compositions, use of such compounds in treating chr...Provided herein are novel benzothiadiazine derivatives as Mas-related G protein-coupled receptor X2 (MRGPRX2) or MRGX2 (Mas-related Gene X2) antagonists, pharmaceutical compositions, use of such compounds in treating chronic spontaneous urticaria, and processes for preparing such compounds.
ACS Med Chem Lett
· 2026 Apr · PMID 41982709
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Provided herein are novel compounds as MALT1 inhibitors, pharmaceutical compositions, use of such compounds in treating cancer, and processes for preparing such compounds.Provided herein are novel compounds as MALT1 inhibitors, pharmaceutical compositions, use of such compounds in treating cancer, and processes for preparing such compounds.
Anwar AF, You L, Degen D
… +4 more, Burns KJ, Garza MJ, Ebright RH, Del Valle JR
ACS Med Chem Lett
· 2026 Mar · PMID 41890570
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Pseudouridimycin (PUM) is a C-nucleoside/peptide antibiotic that selectively inhibits bacterial RNA polymerase (RNAP) and exhibits potent activity against drug-resistant pathogens. However, PUM suffers from chemical inst...Pseudouridimycin (PUM) is a C-nucleoside/peptide antibiotic that selectively inhibits bacterial RNA polymerase (RNAP) and exhibits potent activity against drug-resistant pathogens. However, PUM suffers from chemical instability due to self-immolative cleavage of its central hydroxamate bond. Here, we employed cryo-electron microscopy to determine structures of PUM () and a chemically stabilized des-hydroxy analog of PUM () bound to an RNAP transcription complex. Guided by the observed bound conformation, we developed an efficient solid-phase synthesis of 50 des-hydroxy PUM analogs modified at the Gln residue and Gdn-Gly tail. Several analogs retained low-micromolar RNAP-inhibitory activity, with a -substituted phenyl amidine analog () emerging as the most potent inhibitor (IC = 0.95 μM). These results establish a versatile synthetic platform and structural framework for optimizing stabilized PUM derivatives and provide a foundation for the development of RNAP-targeted therapeutics against resistant bacterial pathogens.
Zorko T, Kogovšek J, Ciber L
… +4 more, Ostojić I, Maraš N, Novinec M, Štefane B
ACS Med Chem Lett
· 2026 Mar · PMID 41847663
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SIRT6, a crucial regulator of aging and cellular homeostasis, represents a promising target for small-molecule activation. In this study, we investigate griseofulvin and its derivatives as novel SIRT6 activators, focusin...SIRT6, a crucial regulator of aging and cellular homeostasis, represents a promising target for small-molecule activation. In this study, we investigate griseofulvin and its derivatives as novel SIRT6 activators, focusing on the recently developed compound forvisirvat, which has progressed to Phase 2 clinical study. Biochemical evaluation revealed that griseofulvin itself possesses strong SIRT6-activating properties, achieving up to 10-fold activity at 100 μM. Modification of the griseofulvin scaffold generally led to reduced activity, prompting a focus on the oxadiazole moiety of forvisirvat. This strategy produced several analogues with higher potency, the most active at 100 μM being -1,3,4-oxadiazolephenyl analog , which achieved 30-fold SIRT6 activation. Compounds bearing -substituted phenyl rings exhibited excellent retention of activity at lower concentrations, with -tolyl derivative being the most potent at 10 μM. Retention of activity at pharmacologically relevant concentrations underscores their potential as potent SIRT6 activators and provides a rationale for continued development as drug candidates.
ACS Med Chem Lett
· 2026 Mar · PMID 41847662
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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 Micropers...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.
ACS Med Chem Lett
· 2026 Mar · PMID 41847661
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This patent describes KLF2-inducing compounds and related pharmaceutical compositions for the treatment of inflammatory diseases and endothelial dysfunction.This patent describes KLF2-inducing compounds and related pharmaceutical compositions for the treatment of inflammatory diseases and endothelial dysfunction.
Swyka RA, Styduhar ED, Wang A
… +26 more, Li X, Zhang K, Witten MR, Zhao P, Liang MZ, Atasoylu O, He P, Soderquist R, Hansbury M, Huo L, Chen H, Zimmer D, Zhang W, Wang K, Volgina A, Epling LB, Crowgey E, Kumari E, Abdollahi A, Zhang G, Rupar M, Schaffer M, Mayes PA, Kim S, Vechorkin O, Wang X
ACS Med Chem Lett
· 2026 Mar · PMID 41847660
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Downregulation of DNA damage repair genes has attracted considerable research attention recently due to the success of poly-(ADP-ribose) polymerase inhibitors. Identification of additional targets and therapies that expl...Downregulation of DNA damage repair genes has attracted considerable research attention recently due to the success of poly-(ADP-ribose) polymerase inhibitors. Identification of additional targets and therapies that exploit synthetic lethality could greatly benefit cancer patients. Cyclin-dependent kinases 12 and 13 (CDK12 and CDK13), which regulate RNA polymerase II (RNA Pol II) and, therefore, gene transcription, represented promising therapeutic targets. Although several inhibitors for these kinases have been disclosed, few have progressed to the clinic. Most existing inhibitors utilize a covalent warhead to obtain potency and selectivity. In this study, we reported the design and development of a series of highly selective noncovalent inhibitors targeting CDK12 and 13. This campaign led to the identification of a lead compound exhibiting outstanding potency and favorable absorption, distribution, metabolism, and excretion profiles, as well as favorable pharmacokinetic properties, thereby demonstrating significant potential for therapeutic applications.
ACS Med Chem Lett
· 2026 Mar · PMID 41847659
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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...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.
Russell IC, Bachurska-Szpala P, van Beek L
… +5 more, Michaelides IN, Phillips C, Snijder A, Stubbs CJ, Collie GW
ACS Med Chem Lett
· 2026 Mar · PMID 41847658
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The c-MET kinase is a driver of many cancers, and as such, there are a number of small molecule inhibitors of this kinase approved for clinical use. In this Microperspective, we provide a structural overview of the molec...The c-MET kinase is a driver of many cancers, and as such, there are a number of small molecule inhibitors of this kinase approved for clinical use. In this Microperspective, we provide a structural overview of the molecular basis by which these drugs inhibit c-MET, focusing on key features contributing to activity, selectivity, and drug resistance. Where necessary, relevant crystal structures not publicly available were determined and are discussed here alongside existing structural data.
ACS Med Chem Lett
· 2026 Mar · PMID 41847657
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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 activi...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 (-) 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. Compounds , , , , , , and were the most active, exhibiting MIC values as low as 0.78 μg mL 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 NO) on the benzene ring showed markedly enhanced antibacterial activity, whereas electron-donating substituents (-OH, -OCH) generally reduced antibacterial activity. Enzyme inhibition assays identified compound as a potent inhibitor of DNA gyrase and compound as a strong topoisomerase IV inhibitor. Importantly, the most active compounds showed a low cytotoxicity toward WI-38 human fibroblast cells.
ACS Med Chem Lett
· 2026 Mar · PMID 41847655
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Recent patent disclosures highlight a conceptual shift in drug discovery, integrating targeted protein degradation with functional precision oncology. IRAK-M and IRAK4 degraders exemplify how innate immune signaling can...Recent patent disclosures highlight a conceptual shift in drug discovery, integrating targeted protein degradation with functional precision oncology. IRAK-M and IRAK4 degraders exemplify how innate immune signaling can be rewired through selective protein removal, while patient-derived microcancer platforms provide a decision framework for rationally deploying such agents. Together, these inventions redefine how molecular precision and biological context converge to guide translational success.
ACS Med Chem Lett
· 2026 Mar · PMID 41847654
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Recent patent disclosures illustrate how modern medicinal chemistry advances by aligning biological insight with chemical modality, formulation rigor, and molecular measurement. Targeted protein degradation to overcome r...Recent patent disclosures illustrate how modern medicinal chemistry advances by aligning biological insight with chemical modality, formulation rigor, and molecular measurement. Targeted protein degradation to overcome resistance, solid-state engineering to ensure sustained pathway suppression, and single-cell genomic profiling to resolve metastatic biology together demonstrate how therapeutic impact emerges when perturbation, delivery, and biological observability are coherently integrated.
Hu Q, Xie H, Zhang Q
… +4 more, Zhu L, Che J, Chen L, Li X
ACS Med Chem Lett
· 2026 Mar · PMID 41847653
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Influenza A virus continues to pose a significant global health threat, causing seasonal epidemics and occasional pandemics. Viral transcription and replication rely on the heterotrimeric polymerase complex where the PB2...Influenza A virus continues to pose a significant global health threat, causing seasonal epidemics and occasional pandemics. Viral transcription and replication rely on the heterotrimeric polymerase complex where the PB2 subunit initiates RNA synthesis through binding to the host mRNA cap structure. In this study, we began with a structure-activity relationship analysis of the pioneering PB2 inhibitor VX-787. Through computer-aided drug design, combined with considerations of molecular docking scores, ADMET property predictions, and a prodrug esterification strategy, we ultimately designed eight novel compounds. Cytopathic effect assays demonstrated that all compounds exhibited superior inhibitory activity against both H1N1 and H3N2 strains compared to oseltamivir acid. In particular, compounds and displayed nanomolar-level activity against H1N1, while compound showed activity against H3N2 superior to that of VX-787. These findings propose a rational design strategy that may offer new avenues for addressing the resistance and metabolic limitations associated with VX-787 and hold potential for advancing the development of next-generation PB2-targeted anti-influenza therapeutics.
ACS Med Chem Lett
· 2026 Mar · PMID 41847652
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Amphotericin B (AmB) is a potent, life-saving antifungal, but its clinical use is limited by toxicity due to poor selectivity for ergosterol over cholesterol. The AmB derivative Am-2-19 (turletricin) exhibits improved er...Amphotericin B (AmB) is a potent, life-saving antifungal, but its clinical use is limited by toxicity due to poor selectivity for ergosterol over cholesterol. The AmB derivative Am-2-19 (turletricin) exhibits improved ergosterol selectivity and reduced toxicity, which is attributed to enhanced ergosterol extraction kinetics via C16-amidation rather than altered sterol binding affinity. Using all-atom molecular dynamics simulations, we reveal key differences in the aggregate morphologies of AmB and Am-2-19 that provide mechanistic insights into the increased ergosterol extraction kinetics. In both the absence and presence of sterols, Am-2-19 aggregates slower than AmB, forming less dense and more solvated aggregates, driven by the hydrogen-bonding capacity of the C16-amidation. , these looser aggregates likely enable a greater exchange of sterols, increasing the likelihood of cholesterol-ergosterol exchange. Our findings provide the first atomistic-level insight into Am-2-19's mechanism, emphasizing the critical role of aggregation in structure-activity relationships in a physiologically relevant solution environment.
Chen YT, Meng FB, Zhuang YQ
… +7 more, Chen ZY, Wang YG, Ning XL, Liu WY, Li R, Wang HL, Li GB
ACS Med Chem Lett
· 2026 Mar · PMID 41847651
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Human secretory glutaminyl cyclase (sQC) and Golgi-resident glutaminyl cyclase (gQC) catalyze the conversion of protein N-terminal glutamine into pyroglutamate (pE), a modification implicated in human diseases including...Human secretory glutaminyl cyclase (sQC) and Golgi-resident glutaminyl cyclase (gQC) catalyze the conversion of protein N-terminal glutamine into pyroglutamate (pE), a modification implicated in human diseases including cancer. Small-molecule inhibitors targeting sQC/gQC represent a promising therapeutic strategy. Here, we report a series of benzyl-5-methyl-1-imidazole derivatives as inhibitors of sQC/gQC. Through structural optimization, we identified , a nanomolar potent inhibitor of both enzymes. Thermal shift assays revealed that enhances the thermal stability of both sQC (Δ = 5.9 °C) and gQC (Δ = 6.0 °C), indicating strong binding interactions. Cellular assays revealed that substantially reduced the level of pE-CD47 modification on the surface of MDA-MB-231 and KYSE30 cells. Furthermore, exhibited antitumor activity in a mouse xenograft tumor model. The results highlight the potential of as a lead compound for developing drugs targeting sQC/gQC-mediated diseases.
Huang X, Huang J, Hong Q
… +8 more, Ou X, Li R, Zong M, Lu T, Zhu Y, Hao H, Wu S, Cui H
ACS Med Chem Lett
· 2026 Mar · PMID 41847650
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Colorectal cancer remains a leading cause of cancer-related mortality. Although KRAS inhibitors have been approved for the treatment of multiple cancers, their clinical efficacy is often limited by KRAS reactivation. SOS...Colorectal cancer remains a leading cause of cancer-related mortality. Although KRAS inhibitors have been approved for the treatment of multiple cancers, their clinical efficacy is often limited by KRAS reactivation. SOS1, a key guanine nucleotide exchange factor involved in KRAS activation and implicated in various malignancies, including colorectal and oral cancers, represents an attractive therapeutic target. In this study, fragment-based virtual screening targeting the Asn879 pocket of SOS1 was performed using the DrugBank database and an in-house chemical library, followed by structure-based optimization and structure-activity relationship analysis. Twenty derivatives were synthesized, among which compound , featuring a 6-methyl-1-imidazo-[4,5-g]-quinazoline scaffold, exhibited the most potent inhibition of the SOS1::KRAS interaction (IC = 4.11 nM). Compound also demonstrated significant antiproliferative activity against DLD-1 CRC cells by inducing apoptosis and G0/G1 cell-cycle arrest. These results identify compound as a promising lead for SOS1-targeted therapy.
Jiang H, Macorano A, Xing E
… +8 more, Jedoui M, Mohammed S, Lee V, Cheng J, McDonough L, Cheng X, Ye J, Li PK
ACS Med Chem Lett
· 2026 Mar · PMID 41847649
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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 fundamen...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 constraintits 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.