ACS Med Chem Lett
· 2026 Apr · PMID 41982732
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Provided herein are novel pyridone carboxamide derived compounds as soluble epoxide hydrolase inhibitors, pharmaceutical compositions, use of such compounds in treating diabetic retinopathy, and processes for preparing s...Provided herein are novel pyridone carboxamide derived compounds as soluble epoxide hydrolase inhibitors, pharmaceutical compositions, use of such compounds in treating diabetic retinopathy, and processes for preparing such compounds.
Shimada K, Gregori-Puigjane E, Stokes ME
… +2 more, Skouta R, Stockwell BR
ACS Med Chem Lett
· 2026 Apr · PMID 41982731
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Small molecules frequently induce heterogeneous cell-death programs, complicating the mechanistic interpretation and optimization. Here, we investigate the ferroptotic and necrotic activities of the lethal small molecule...Small molecules frequently induce heterogeneous cell-death programs, complicating the mechanistic interpretation and optimization. Here, we investigate the ferroptotic and necrotic activities of the lethal small molecule CIL56 and related analogs. Although structurally similar, these compounds induce chemically separable death phenotypes. A phenotypic suppressor screen further identified distinct sets of small molecules that selectively attenuate ferroptotic or necrotic death. Classification of suppressor compounds based on shared ligand-based target predictions suggested nonoverlapping groups of candidate protein targets linked to each death modality. Together, these results show that integrating phenotypic screening with suppressor classification and target prediction can improve the interpretability of small-molecule phenotypic screens by prioritizing candidate proteins and pathways underlying the observed biological response.
He Y, Gu J, Hua L
… +6 more, Zhai D, Huang Q, Pei J, You Q, Zhang Q, Wang L
ACS Med Chem Lett
· 2026 Apr · PMID 41982730
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Small-molecule modulators targeting the N-terminal tetratricopeptide repeat (TPR) domain of protein phosphatase 5 (PP5) remain largely unexplored. Here, we report the repurposing of ilaprazole as a PP5 TPR domain binder...Small-molecule modulators targeting the N-terminal tetratricopeptide repeat (TPR) domain of protein phosphatase 5 (PP5) remain largely unexplored. Here, we report the repurposing of ilaprazole as a PP5 TPR domain binder identified via a fluorescence polarization-based competitive screen. Biophysical assays and molecular docking supported the interaction within the PP5 TPR binding pocket, revealing key structural features distinguishing ilaprazole from related proton pump inhibitors. In KRAS mutant colorectal cancer cells, ilaprazole engaged cellular PP5, leading to reduced RAF stability and suppressed mitogen-activated protein kinase (MAPK) signaling. While exhibiting minimal single-agent effects, ilaprazole sensitized cells to the MEK inhibitor binimetinib. These results validate the PP5 TPR domain as a druggable site and establish ilaprazole as a lead scaffold for pharmacological modulation of PP5-associated MAPK signaling.
Reddy Guduru SK, Caldwell JP, Digianantonio KM
… +30 more, Prophet SM, Yang S, Gareiss P, Jones C, Harbin A, Driscoll B, Karim MF, Scott A, Patel A, Chapman AE, Crandall M, Miklossy G, Barczak NT, Stroppa AP, Corradi JP, Clark JJ, Chung MK, Reinhardt NR, Butcher WE, Wilson R, Stiff C, Fathizadeh A, Yuan L, Wang G, Dong H, Beno BR, Zimmermann K, Langley DR, Cacace AM, Békés M
ACS Med Chem Lett
· 2026 Apr · PMID 41982729
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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...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.
Claton LE, Reddy KHV, Gaines SN
… +13 more, Brown SD, Schluckwerder BC, Elam GT, Gendler DS, Ganz AS, McPhaul LC, Rangel AE, Noland JK, Jackson FA, Bobo GG, Yusufji AJ, Simanek EE, Lee KM
ACS Med Chem Lett
· 2026 Apr · PMID 41982728
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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...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 -butyl ester or -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.
Xie L, Zhu M, Zhao T
… +6 more, Pei Y, Wei B, Zhu S, Chen J, Zhang H, Zhou J
ACS Med Chem Lett
· 2026 Apr · PMID 41982727
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Monoclonal antibodies (mAbs) targeting programmed cell death protein-1 and its ligand 1 (PD-1/PD-L1) have demonstrated significant efficacy in cancer immunotherapy. However, mAbs still have limitations in pharmacokinetic...Monoclonal antibodies (mAbs) targeting programmed cell death protein-1 and its ligand 1 (PD-1/PD-L1) have demonstrated significant efficacy in cancer immunotherapy. However, mAbs still have limitations in pharmacokinetic properties and immunogenicity. As a complementary approach, PD-1/PD-L1 small molecule inhibitors have thus become an attractive direction for development. In this study, a series of novel small molecule compounds based on an oxadiazole-biphenyl scaffold were designed and synthesized. Biological evaluation showed that compound exhibited the most potent activity of the PD-1/PD-L1 interaction (IC = 5.3 nM). At the cellular level, significantly enhanced the immune-killing activity of peripheral blood mononuclear cells (PBMCs) against MDA-MB-231 tumor cells and restored T-cell immune function by promoting IFN-γ secretion. These results indicate that compound is a promising PD-1/PD-L1 small molecule inhibitor for further development and optimization.
ACS Med Chem Lett
· 2026 Apr · PMID 41982726
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Provided herein are novel compounds as PTPN2 inhibitors, pharmaceutical compositions, use of such compounds in treating cancer, and processes for preparing such compounds.Provided herein are novel compounds as PTPN2 inhibitors, pharmaceutical compositions, use of such compounds in treating cancer, and processes for preparing such compounds.
ACS Med Chem Lett
· 2026 Apr · PMID 41982725
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This patent discloses a series of substituted indazole compounds as novel inhibitors of KRAS, with potential utility as anticancer therapeutics. The invention describes the chemical structures of these substituted indazo...This patent discloses a series of substituted indazole compounds as novel inhibitors of KRAS, with potential utility as anticancer therapeutics. The invention describes the chemical structures of these substituted indazoles, their pharmaceutical compositions, and methods of use for treating KRAS-driven malignancies. The disclosed compounds are designed to modulate oncogenic KRAS signaling and may offer a new therapeutic strategy for cancers associated with KRAS mutations.
ACS Med Chem Lett
· 2026 Apr · PMID 41982724
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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...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, -(benzothiazol-2-yl)-trichloroacetamidine, with potent activity against multidrug-resistant . Focused phenotypic screening of 304 -(azol-2-yl)-imidamide derivatives identified -(benzothiazol-2-yl)-trichloroacetamidine as a . 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 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 possesses desirable properties, including a 3 h half-life, good systemic exposure, and no observable toxicity. Collectively, these findings establish -(benzothiazol-2-yl)-trichloroacetamidines as a promising new class of antibacterial agents for combating multidrug-resistant infections.
ACS Med Chem Lett
· 2026 Apr · PMID 41982723
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The invention in this patent application relates to 9-purine derivatives represented herein generally by formula 1. These compounds are inhibitors of the DNA polymerase theta (Polθ or POLQ), and they can potentially prov...The invention in this patent application relates to 9-purine derivatives represented herein generally by formula 1. These compounds are inhibitors of the DNA polymerase theta (Polθ or POLQ), and they can potentially provide useful therapy for the treatment of cancer.
Shimizu T, Tago K, Yokoyama M
… +4 more, Nakamura K, Tokieda-Tanoue S, Kita A, Miyazaki S
ACS Med Chem Lett
· 2026 Apr · PMID 41982722
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We hypothesized that the formation of biofilms contributes to the onset of inflammatory bowel disease and, thus, attempted to develop biofilm inhibitors as potential treatment options. We identified a compound () with bi...We hypothesized that the formation of biofilms contributes to the onset of inflammatory bowel disease and, thus, attempted to develop biofilm inhibitors as potential treatment options. We identified a compound () with biofilm inhibitory activity in vitro; however, its rate of delivery to the target site, the colon, was low due to its high lipophilicity and low solubility. To improve the colon delivery rate, we considered a prodrug approach through glucuronidation. The glucuronide () showed a significant improvement in the in vivo colon delivery rate by avoiding absorption in the small intestine through a reduction in membrane permeability. Furthermore, in a murine disease model featuring dextran sulfate sodium-induced colitis, we confirmed that compound increased the length of the colon approximately three times more than compound did on a dosage basis.
Li S, Yang X, Yin W
… +4 more, Zhang W, Li Z, Hu J, Li Y
ACS Med Chem Lett
· 2026 Apr · PMID 41982721
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Simultaneous inhibition of cell cycle CDKs and transcriptional CDKs may provide a novel strategy for cancer therapy. Starting from a pan-CDK inhibitor, a series of novel 2-((4-substitutedphenyl)-amino)-pyrrolo-[2,3-]-pyr...Simultaneous inhibition of cell cycle CDKs and transcriptional CDKs may provide a novel strategy for cancer therapy. Starting from a pan-CDK inhibitor, a series of novel 2-((4-substitutedphenyl)-amino)-pyrrolo-[2,3-]-pyrimidine derivatives were synthesized and evaluated for their inhibition effects on cellular proliferation and CDK enzymatic activity. Several new derivatives exhibited significantly improved profiles in terms of antitumor potency, metabolic stability, and kinase selectivity. Further biological and pharmacokinetic evaluation confirmed that derivative (LS-Q2) is a novel, orally bioavailable, and highly selective CDK4/9 inhibitor with potent antiproliferative activity against various tumor cells. Moreover, LS-Q2 exhibited significant synergistic antitumor effects when combined with the BET and Bcl-2 inhibitors. The discovery of LS-Q2 provides promising next-generation CDK inhibitor leads for the treatment of malignant solid tumors beyond breast cancer and highlights the potential of orally available and selective CDK4/9 inhibitors in cancer treatment.
ACS Med Chem Lett
· 2026 Apr · PMID 41982720
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Provided herein are novel compounds, pharmaceutical compositions, use of such compounds in treating Huntington's disease, and processes for preparing such compounds.Provided herein are novel compounds, pharmaceutical compositions, use of such compounds in treating Huntington's disease, and processes for preparing such compounds.
ACS Med Chem Lett
· 2026 Apr · PMID 41982719
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Growth hormone secretagogue receptor (GHSR) is expressed in a variety of peripheral organs, the brain, and tumor tissues, making it an important molecular target for both translational imaging and mechanistic studies of...Growth hormone secretagogue receptor (GHSR) is expressed in a variety of peripheral organs, the brain, and tumor tissues, making it an important molecular target for both translational imaging and mechanistic studies of GHSR-related physiology and pathology. To date, several GHSR-targeted PET probes have been developed to support disease diagnosis and fundamental research on GHSR function. Recently, a study revealed PET tracer [F]-AQ-12 demonstrated favorable properties, including low lipophilicity, comparable binding affinity to existing ligands, and notably higher pancreatic uptake in GHSR-expressing tissue. Importantly, systematic structure-activity relationship analyses of this compound have been clearly delineated, providing valuable insights to guide further ligand optimization and GHSR-targeted drug development.
Yoshida S, Kondo N, Uehara S
… +5 more, Yoshimura N, Sako Y, Yamamoto S, Kitade M, Tachibana Y
ACS Med Chem Lett
· 2026 Apr · PMID 41982718
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Nicotinamide -methyltransferase (NNMT) has emerged as a regulator of cellular methylation, epigenetic remodeling, and energy homeostasis. Its aberrant expression has been implicated in cancer, metabolic disorders, and re...Nicotinamide -methyltransferase (NNMT) has emerged as a regulator of cellular methylation, epigenetic remodeling, and energy homeostasis. Its aberrant expression has been implicated in cancer, metabolic disorders, and renal diseases. Although several NNMT inhibitors have been reported, most lack selectivity, cellular activity, or favorable pharmacokinetic properties. Here, we describe the discovery and optimization of a novel non-SAM-mimetic bisubstrate inhibitor of NNMT originating from high-throughput screening. Guided by structure-based design, systematic modifications of hit compound yielded lead compound with over 1000-fold improved potency (IC for compounds and = 10 μM and 0.0084 μM, respectively). Compound exhibited sub-micromolar cell-based activity and high selectivity for a subfamily of methyltransferases. In rodents, compound exhibited pronounced renal distribution and moderate bioavailability, while achieving dose-dependent renal NNMT inhibition in a renal fibrosis model. These results highlight compound as a promising probe and a starting point for NNMT-targeted drug discovery.
Riedel M, Zimmer C, Häberli C
… +2 more, Keiser J, Kersten C
ACS Med Chem Lett
· 2026 Apr · PMID 41982717
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Schistosomiasis remains a major global health challenge, and the threat of emerging praziquantel resistance highlights the need for new therapeutic strategies. Here, the -myristoyltransferase was evaluated as a potential...Schistosomiasis remains a major global health challenge, and the threat of emerging praziquantel resistance highlights the need for new therapeutic strategies. Here, the -myristoyltransferase was evaluated as a potential drug target. Six reported NMT inhibitors were tested for NMT inhibition and binding, with two compounds showing low nanomolar potency. These also inhibited NMT of and , and exhibit favorable drug-like physicochemical properties. In addition, antiparasitic activity against newly transformed and adult worms was investigated. The results confirm NMT as a viable target for drug discovery against schistosomiasis and provide a basis for further optimizations of NMT inhibitors.
ACS Med Chem Lett
· 2026 Apr · PMID 41982716
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The invention in this patent application relates to condensed bicyclic heteroaromatic compounds represented herein generally by formula 1. These compounds possess activities as inhibitors of TEAD, and may potentially pro...The invention in this patent application relates to condensed bicyclic heteroaromatic compounds represented herein generally by formula 1. These compounds possess activities as inhibitors of TEAD, and may potentially provide therapy for treating cancer.
Sells CA, Kostyo JH, Gaykar RN
… +3 more, Kara MI, Lallande AT, Kane RR
ACS Med Chem Lett
· 2026 Apr · PMID 41982715
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We have previously reported two prodrug designs for the delivery of the potent TLR4 inhibitor TAK-242. Our initial design was used to covalently link TAK-242 to pancreatic islets using a linker to afford sustained delive...We have previously reported two prodrug designs for the delivery of the potent TLR4 inhibitor TAK-242. Our initial design was used to covalently link TAK-242 to pancreatic islets using a linker to afford sustained delivery of the active drug after transplant. Those drug-eluting islets provided local inhibition of TLR4-linked inflammation and improved islet graft survival. Here, we describe a third family of TAK-242 prodrugs featuring two rate modulating sites, a self-immolative aniline-stabilized methylene spacer bonded directly to the sulfonamide nitrogen, an alcohol tether for bioconjugation, and a β-eliminative aryl-sulfone "trigger". These prodrugs rapidly release TAK-242 after activation by β-elimination and a rapid subsequent 1,2-elimination, cleanly releasing the drug without detectable intermediates. This manuscript reports the preparation and characterization of a series of methylene-linked TAK-242 prodrugs, evaluating the impact of various modifications on drug release kinetics.
González-Gutiérrez JP, Castillo-Ríos DA, González-Gutiérrez IA
… +4 more, Palma-Ruíz DR, Vidal-Beltrán IA, Carvacho IV, Hinostroza FA
ACS Med Chem Lett
· 2026 Apr · PMID 41982714
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The muscarinic acetylcholine M1 receptor (M1-mAChR) is a key regulator of cognitive processes and remains an attractive target for the modulation of central cholinergic signaling. In this study, tetrahydroisoquinoline-de...The muscarinic acetylcholine M1 receptor (M1-mAChR) is a key regulator of cognitive processes and remains an attractive target for the modulation of central cholinergic signaling. In this study, tetrahydroisoquinoline-derived ligands (THQ140, THQ790) and a structurally related compound (QPB) were evaluated for their ability to modulate M1-mAChR activity. Intracellular Ca imaging in HEK-293 cells expressing human M1-mAChR revealed distinct functional profiles, including partial agonist activity and limited or noncooperative modulation of ACh-induced signaling. In contrast to the prototypical M1 positive allosteric modulator benzyl quinolone carboxylic acid (BQCA), which displays minimal intrinsic agonism and strong positive cooperativity with ACh, the compounds reported here exhibited direct receptor activation with weaker or absent potentiation. Molecular docking and molecular dynamics simulations supported preferential interaction at a nonorthosteric region of the receptor. In addition, analysis of single-nucleus RNA sequencing data sets confirmed robust expression in neuronal populations of healthy and Alzheimer's disease brains, supporting the continued relevance of M1-mAChR as a pharmacological target.
Francisco S, Apprato G, Rossi Sebastiano M
… +2 more, Ermondi G, Caron G
ACS Med Chem Lett
· 2026 Apr · PMID 41982713
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The development of CNS-active PROTACs is limited by the blood-brain barrier (BBB). This Microperspective briefly reviews BBB physiology and critically evaluates current , , and models used to assess brain penetration. T...The development of CNS-active PROTACs is limited by the blood-brain barrier (BBB). This Microperspective briefly reviews BBB physiology and critically evaluates current , , and models used to assess brain penetration. These considerations enable a unified analysis of the 30 published 30 CNS-targeted degraders compiled here for the first time, highlighting the lack of a consistent design strategy and offering perspectives for future programs.