Clarke JG, Dutta N, Nickel MS
… +11 more, Wang Z, Kim J, Media J, Coppage DA, McCauley EP, Gerke JA, Anderson MO, Higuchi-Sanabria R, Valeriote FA, Crews P, Johnson TA
ACS Med Chem Lett
· 2026 Jun · PMID 42305219
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Semisynthetic modification of mycothiazole () with Meerwein's salt to generate a more stable and/or potent analog than 8--acetylmycothiazole () unexpectedly yielded diastereomers devoid of the diene. Analysis of NMR, HR-...Semisynthetic modification of mycothiazole () with Meerwein's salt to generate a more stable and/or potent analog than 8--acetylmycothiazole () unexpectedly yielded diastereomers devoid of the diene. Analysis of NMR, HR-LCMS, and optical rotation confirmed the structures as (-)-4,4-hydroxy-methyl-(5)-(8)-(14)-mycothiazole (, : dr 1:1.1). Both compounds demonstrated reduced stability versus or . Cytotoxicity evaluation of versus indicated 5-fold differences in potency against pancreatic (IC = 7.81, 1.34 μM; PANC-1) and glioblastoma (IC = 8.53, 1.63 μM; U251N) cancer cells, respectively. In vivo evaluation of and , using in aging studies, indicated not inhibited mitochondrial function, while neither affected lifespan compared to . These results demonstrate the diene of may be required for its picomolar cytotoxic potency to cancer cells or effects on lifespan in , and minor variations in the stereochemistry of this chemotype merit further investigation to modulate its bioactivity.
Roy A, Beniwal N, Shome A
… +2 more, Rengan AK, Chinta JP
ACS Med Chem Lett
· 2026 Jun · PMID 42305218
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Higher intracellular ROS concentration of TNBC cells may serve as a therapeutic target to develop antioxidant-based drugs to treat such cancers. The HCA-conjugated terpyridine-copper analogues are reported for the select...Higher intracellular ROS concentration of TNBC cells may serve as a therapeutic target to develop antioxidant-based drugs to treat such cancers. The HCA-conjugated terpyridine-copper analogues are reported for the selective treatment of TNBC, but the investigation on the antiproliferative activities remains to be elucidated. Herein, a set of terpyridine-conjugated HBA and HCA derivatives and their ROS-induced products were isolated and evaluated for their anti-TNBC properties. studies on 4T1 cell lines revealed that the ROS-oxidized intermediates showed potential therapeutic activity to cause the antiproliferative activity of their parent analogues. Further, the presence of copper was also found to enhance the anticancer activity of these derivatives with high selectivity toward TNBC. Due to the presence of natural antioxidant residues, all these derivatives were found to be biocompatible, as studied over NIH/3T3 cell lines. These results illustrate the involvement of ROS-generated cytotoxic intermediates, responsible for the therapeutic applicability of natural antioxidant-based derivatives toward TNBC.
Baroni C, Ferraroni M, Supuran CT
… +1 more, Angeli A
ACS Med Chem Lett
· 2026 Jun · PMID 42305217
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Pevonedistat (MLN4924) is a first-in-class inhibitor of the NEDD8-activating enzyme that blocks protein neddylation and exhibits antitumor activity in multiple clinical phases. Here, we report a previously unrecognized a...Pevonedistat (MLN4924) is a first-in-class inhibitor of the NEDD8-activating enzyme that blocks protein neddylation and exhibits antitumor activity in multiple clinical phases. Here, we report a previously unrecognized and isoform-selective inhibitory profile of pevonedistat against the tumor-associated isoforms human carbonic anhydrase IX and XII (hCA IX and XII). To elucidate the structural basis of this selectivity, X-ray crystal structures were determined for pevonedistat in complex with hCA I, hCA II, and an engineered hCA II variant mimicking hCA XII. These findings provide a mechanistic explanation for the known preferential partitioning of pevonedistat into whole blood via binding to erythrocyte CAs and suggest that CA inhibition may contribute to its antitumor activity in hypoxic tumor microenvironments where hCA IX and XII are overexpressed. This study reveals a dual functional profile for pevonedistat, linking neddylation inhibition with selective targeting of tumor-associated CAs and offers to exploit this synergy in anticancer drug design.
Yap JL, Lovett G, Mason JW
… +24 more, Tucker J, Boe D, Chen A, Coffman KJ, DaSilva J, Dickinson T, Frattini V, Guan Y, Guiraldelli MF, Hou XJ, Jasti J, Kenton NT, Machin-Rivera R, Marroquin L, McClendon CL, McLaughlin M, Pecora A, Robinson MC, Stock IA, Tria GS, Tuttle J, Young JA, Zhang L, Lee AA
ACS Med Chem Lett
· 2026 Jun · PMID 42305216
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Polo-like kinases (PLKs) are a family of closely related serine/threonine kinases responsible for regulating cell cycle processes and proliferation. While PLK1 inhibitors have led to clinical candidates for oncology, the...Polo-like kinases (PLKs) are a family of closely related serine/threonine kinases responsible for regulating cell cycle processes and proliferation. While PLK1 inhibitors have led to clinical candidates for oncology, the biological function of other PLKs is relatively unknown, in part, because there is a dearth of selective tool compounds. Herein we report the parallel medicinal chemistry (PMC) and structure-assisted discovery of potent and selective PLK3 inhibitors with favorable drug-like properties. We employed computational tools to reveal subtly different pharmacophore features within homologous binding sites of PLKs. These preferences were then exploited via a PMC approach starting from in-house high-throughput screening hits, resulting in selective chemical probes that help elucidate the complexities of PLK biology. Further, by profiling compounds with a spectrum of PLK selectivities, our work demonstrates the relationship between inhibition of specific PLK isoforms and resulting toxicities.
ACS Med Chem Lett
· 2026 Jun · PMID 42305215
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Recent advances in serotonergic drug discovery and neuromodulation converge on a central goal: inducing therapeutic neuroplasticity without undesirable perceptual effects. Structurally constrained receptor agonists, biol...Recent advances in serotonergic drug discovery and neuromodulation converge on a central goal: inducing therapeutic neuroplasticity without undesirable perceptual effects. Structurally constrained receptor agonists, biologically validated neuroplastogens, and adaptive transcutaneous stimulation systems together define a multiscale framework that integrates molecular precision, cellular remodeling, and physiological regulation, enabling controlled and reproducible neuropsychiatric treatment outcomes.
ACS Med Chem Lett
· 2026 Jun · PMID 42305214
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Targeted protein degradation and biomarker-guided therapy offer complementary strategies for controlling transcription-driven cancers. One approach eliminates BCL6 through heterobifunctional degraders, while another defi...Targeted protein degradation and biomarker-guided therapy offer complementary strategies for controlling transcription-driven cancers. One approach eliminates BCL6 through heterobifunctional degraders, while another defines S100A8/A9-centered biomarkers that predict response to BET inhibition. Together, they reveal how combining protein elimination with molecular stratification can overcome resistance, refine patient selection, and enable more durable therapeutic responses in oncology.
Xia Z, Wu T, Hu C
… +8 more, Wu C, Wang H, Liu Q, Qi Z, Wang A, Liu Q, Liang X, Liu J
ACS Med Chem Lett
· 2026 Jun · PMID 42305213
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Bone marrow tyrosine kinase gene in chromosome X protein (BMX) plays a critical role in the initiation, progression, and development of castration-resistant prostate cancer. While several ATP-competitive BMX inhibitors h...Bone marrow tyrosine kinase gene in chromosome X protein (BMX) plays a critical role in the initiation, progression, and development of castration-resistant prostate cancer. While several ATP-competitive BMX inhibitors have been developed as cellular chemical tools to investigate the function of BMX, they are unable to target the nonenzymatic roles of BMX. Proteolysis-targeting chimeras (PROTACs) represent an emerging technology that enables the rapid and complete degradation of target proteins. Here, we describe the design, synthesis, and characterization of BMX PROTACs by conjugating the BMX and cereblon (CRBN) ligands. In LNCaP clone FGC cells, the representative compound () induced time- and dose-dependent BMX degradation with nanomolar DC values, a process mediated by the CRBN pathway and the proteasome system. It exhibited potent antiproliferative effects on prostate cancer cells. These results indicate that BMX-PROTACs are potential therapeutic candidates for prostate cancer.
Huang C, Liang M, Zhang P
… +2 more, Liu G, Liao C
ACS Med Chem Lett
· 2026 Jun · PMID 42305212
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Methylthioadenosine (MTA) accumulation inhibits the protein arginine methyltransferase 5 (PRMT5), rendering cancers harboring methylthioadenosine phosphorylase (MTAP) deletion vulnerable; thus, PRMT5 inhibitors hold prom...Methylthioadenosine (MTA) accumulation inhibits the protein arginine methyltransferase 5 (PRMT5), rendering cancers harboring methylthioadenosine phosphorylase (MTAP) deletion vulnerable; thus, PRMT5 inhibitors hold promise for treating these cancers. In this letter, a structure-guided design approach yielded many novel highly potent and selective MTA-cooperative PRMT5 inhibitors featuring a core structure of 4-amino--((5-ethynylpyridin-2-yl)-methyl)-1-methyl-1-pyrazolo-[4,3-]-quinoline-8-carboxamide. Among them, compound demonstrated significant inhibitory activity and selectivity against HCT116 MTAP-del cells. Further biological evaluations demonstrated that this compound exerts potent inhibitory effects across multiple MTAP-null cancer cell lines, alongside robust enzymatic inhibition and favorable pharmacokinetic profiles consistent with drug-like properties. Notably, compound displayed prominent antitumor potency in a HCT116 MTAP/ CDX model. Collectively, these results establish compound as a highly effective and selective MTA-cooperative PRMT5 inhibitor, presenting a promising candidate for future therapeutic development.
Lambrecht MJ, Liang J, Ung PM
… +32 more, Huestis MP, Zhu BY, Barton LM, Castanedo GM, Zbieg JR, Larouche-Gauthier R, Jakalian A, Leclerc JP, Yadav A, Haghshenas P, Aubert-Nicol S, Ismaili H, Zhao L, Leblanc M, Wang J, Wang S, Wang Q, Garner T, Tan S, Prangley M, Broccatelli F, Pang J, Murray J, Yu C, Hsu P, Rutz S, Kakiuchi-Kiyota S, Ishizuka I, Leung DH, Kou P, Bao L, Wang X
ACS Med Chem Lett
· 2026 Jun · PMID 42305211
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Casitas B-lineage lymphoma-b (Cbl-b), an E3 ubiquitin ligase, is a key negative regulator of immune function, and its inhibition is a promising strategy for cancer immunotherapy. Here, we show the optimization of a serie...Casitas B-lineage lymphoma-b (Cbl-b), an E3 ubiquitin ligase, is a key negative regulator of immune function, and its inhibition is a promising strategy for cancer immunotherapy. Here, we show the optimization of a series of inactive-state Cbl-b inhibitors to improve their potency and pharmacokinetic properties. Through systematic modification of a benzylic amine and a linker region, compound was identified, which demonstrates a favorable balance of biochemical potency, cellular activity, and ADME properties. Despite exhibiting high IV clearance , compound achieved oral exposures sufficient to demonstrate significant tumor growth inhibition in a murine CT26 colon-cancer model.
ACS Med Chem Lett
· 2026 Jun · PMID 42305210
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Provided herein are novel compounds as TREM2 modulators, pharmaceutical compositions, use of such compounds in treating Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, frontotemporal dementia, an...Provided herein are novel compounds as TREM2 modulators, pharmaceutical compositions, use of such compounds in treating Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, frontotemporal dementia, and Nasu-Hakola disease, and processes for preparing such compounds.
Nguyen N, Masui C, Childs A
… +3 more, Barlow A, Chen T, Huestis MP
ACS Med Chem Lett
· 2026 Jun · PMID 42305209
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Commercially available lab equipment was successfully integrated to enable visible-range photochemistry in a high-throughput 96-well screening format with magnetic stirring. Precise temperature control with maximal throu...Commercially available lab equipment was successfully integrated to enable visible-range photochemistry in a high-throughput 96-well screening format with magnetic stirring. Precise temperature control with maximal throughput was achieved by positioning the light source above the reaction mixtures and a cooling source below. This platform was benchmarked against other state-of-the-art commercial options using the Doyle-MacMillan reaction. Establishing a highly irradiated, temperature-controlled micromole-scale high-throughput experimentation (HTE) reaction screening protocol in a standard 96-well format could potentially accelerate modern reaction optimization in both medicinal and process chemistry.
Therrien E, Feng S, Amberg-Johnson K
… +12 more, Shaikh N, Patil P, Majumdar S, Abraham N, Eiler D, Kutter S, Albanese SK, Haldar S, Kroeck KG, Atsriku C, Gerasyuto AI, Levinson AM
ACS Med Chem Lett
· 2026 Jun · PMID 42305208
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The clinical emergence of diverse c-MET mutations with resistance to approved inhibitors has created an urgent demand for next-generation inhibitors with efficacy against c-MET-resistant mutations while maintaining c-MET...The clinical emergence of diverse c-MET mutations with resistance to approved inhibitors has created an urgent demand for next-generation inhibitors with efficacy against c-MET-resistant mutations while maintaining c-MET wild-type (WT) potency, selectivity over other kinases, and brain penetration. Here, we report a novel chemical series discovered through iterative core enumeration and decoration guided by free energy perturbation calculations. Type-III inhibitor demonstrated potent activity against both WT and c-MET with the D1228V resistance mutation with promising physicochemical properties, laying the foundation for the development of brain-penetrant therapies targeting c-MET-driven cancers.
ACS Med Chem Lett
· 2026 Jun · PMID 42305207
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Amino-acid-derived arylpropionamide androgen receptor (AR) modulators, termed EPic AR modulators, have been developed through an efficient 2-3 step synthesis from commercially available enantioenriched amino acid startin...Amino-acid-derived arylpropionamide androgen receptor (AR) modulators, termed EPic AR modulators, have been developed through an efficient 2-3 step synthesis from commercially available enantioenriched amino acid starting materials. This modular route delivers gram-scale quantities of the targets in excellent yield and with high enantiomeric excess (>99% ee), overcoming limitations in the enantioselective preparation of selective androgen receptor modulators (SARMs) and antiandrogens (AAs) while unlocking the previously invariant α-amido heteroatom for structural diversification. Binding assays reveal strong AR affinity for several analogs. Initial validation through cellular reporter assays demonstrates tunable antagonism, with select compounds exhibiting a distinctive biphasic profile: low-efficacy partial agonism at low concentrations that transitions to antagonism at higher doses. These results establish a powerful, operationally simple platform for the rapid generation of stereochemically defined AR modulators, offering new opportunities for next-generation therapeutics in muscle-wasting disorders, oncology supportive care, and androgen-related diseases.
ACS Med Chem Lett
· 2026 Jun · PMID 42305206
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Provided herein are novel tricyclic compounds as 5-HT2A receptor agonists, pharmaceutical compositions, use of such compounds in treating depression, anxiety, substance abuse and headaches, and processes for preparing su...Provided herein are novel tricyclic compounds as 5-HT2A receptor agonists, pharmaceutical compositions, use of such compounds in treating depression, anxiety, substance abuse and headaches, and processes for preparing such compounds.
Grams ES, Ramos AS, da Silva FF
… +20 more, Perelló MA, de Matos Czeczot A, Maia AM, Caetano HA, Altenhofen S, Paz JD, Gonçalves GA, Liu XG, Repasy T, Klein LD, Polesello GP, Sanchez Ferreira CA, de Oliveira SD, Stieler R, Silva SME, Bonan CD, Bizarro CV, Basso LA, Parish T, Machado P
ACS Med Chem Lett
· 2026 Jun · PMID 42305205
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The development of new chemotypes active against drug-resistant remains a major priority in tuberculosis drug discovery. Herein, a series of 4-aminoalkylquinolines was designed and synthesized to improve antimycobacteri...The development of new chemotypes active against drug-resistant remains a major priority in tuberculosis drug discovery. Herein, a series of 4-aminoalkylquinolines was designed and synthesized to improve antimycobacterial potency and permeability. Structure-activity relationship studies identified key contributions of alkyl substitution at C-2 and hydrophobic terminal phenyl substituents. The most active derivatives exhibited submicromolar to low-nanomolar activity (MIC = 0.02-0.05 μM) and retained activity against multidrug-resistant clinical isolates. Evaluation against a QcrB strain indicated reduced susceptibility, consistent with inhibition of the cytochrome bc complex. Single-crystal X-ray diffraction confirmed the structure of a representative compound. Selected molecules showed favorable selectivity in Vero and HepG2 cells and limited activity against non-mycobacterial bacteria. In vitro ADME profiling revealed pH-dependent solubility, good permeability, and rapid metabolic turnover. Zebrafish assays showed no detectable cardiac effects up to 0.3 μM. Overall, this chemotype represents a promising scaffold for antitubercular agents targeting mycobacterial respiration.
ACS Med Chem Lett
· 2026 Jun · PMID 42305204
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We describe the synthesis and biochemical characterization of a series of compounds derived from a previously reported pyrazolopyrimidine-based KRAS inhibitor [ACS Omega2019, 4 (2), 2921-2930]. Dozens of derivatives were...We describe the synthesis and biochemical characterization of a series of compounds derived from a previously reported pyrazolopyrimidine-based KRAS inhibitor [ACS Omega2019, 4 (2), 2921-2930]. Dozens of derivatives were made primarily by modifying the substituents of the pyrazolo-pyrimidine core with the goal of increasing binding affinity to KRAS and improving inhibitory activities against wild-type and oncogenic mutants of KRAS using biophysical measurements and cell proliferation assays. We show that while many of the new compounds exhibited a dramatic increase in binding affinity to KRAS, in many cases, that did not translate into improved potency in inhibiting cell growth. Considering the high binding affinities (up to single-digit nanomolar) and low micromolar inhibitory activities across multiple KRAS mutant cancer cells, we propose that these new derivatives will serve as useful investigational agents for KRAS studies or as starting points for further derivatization and structure-activity relationship studies.
Halpern OS, Reznik SK, Zhang X
… +11 more, Jiang W, Posy SL, Hua J, Everlof G, Guarino VR, Malmstrom S, Sum C, Schumacher WA, Yang J, Wexler RR, Priestley ES
ACS Med Chem Lett
· 2026 Jun · PMID 42305203
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Lead optimization of PAR4 antagonist was carried out with the aim of improving the aqueous solubility to obviate the need for enabled formulations. Structural modifications, including deannulation and introduction of po...Lead optimization of PAR4 antagonist was carried out with the aim of improving the aqueous solubility to obviate the need for enabled formulations. Structural modifications, including deannulation and introduction of polar functionality, led to lead compound . Compound demonstrated potent and platelet aggregation inhibition and oral exposure when dosed from an enabled solubilizing PEG formulation. It was demonstrated that when a phosphate ester prodrug was appended to the terminal hydroxy group of to obtain compound , the aqueous thermodynamic solubility in 50 mM phosphate buffer improved >1200-fold. Oral dosing of in rats delivered the parent compound with 44% relative bioavailability to the enabled parent. Although this represented a reduction in total exposure relative to dosing the parent from the enabled formulation, likely due to incomplete absorption or phosphate ester cleavage, the prodrug successfully provided systemic coverage without solubilizing excipients.
Thacker PS, Gao Y, McPherson L
… +6 more, Lee A, Averill AM, Pratihar S, Doublié S, Ford JM, Kool ET
ACS Med Chem Lett
· 2026 Jun · PMID 42305202
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Elevated activity of DNA repair enzymes that surveil pyrimidine damage has been associated with resistance to antitumor therapies. The DNA base excision repair (BER) enzyme SMUG1 recognizes and excises a number of modifi...Elevated activity of DNA repair enzymes that surveil pyrimidine damage has been associated with resistance to antitumor therapies. The DNA base excision repair (BER) enzyme SMUG1 recognizes and excises a number of modified and damaged pyrimidines that arise in cellular DNA, including deoxyuridine and 5-hydroxymethyl-dU, as well as the cytotoxic antitumor pyrimidine 5-fluorodeoxyuridine (5-FdU). Here we report the discovery and development of the first SMUG1 inhibitor scaffolds, derived from a small molecule sphingosine kinase inhibitor identified as a hit in assays against the DNA repair enzyme. Partial structural optimization resulted in compound SU0617, which inhibits SMUG1 with IC = 1.5 ± 0.1 μM and has ablated kinase inhibitory activity. We expect that the new inhibitor can be useful as a tool in studies of the overlapping substrate preferences of base excision repair enzymes and in the study of the pathways involved in responses to therapeutic nucleoside drugs.
ACS Med Chem Lett
· 2026 Jun · PMID 42305201
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Provided herein are novel 3-aza-bicyclo[3.3.0]-octane compounds as ERK5 inhibitors, pharmaceutical compositions, use of such compounds in treating cancer, and processes for preparing such compounds.Provided herein are novel 3-aza-bicyclo[3.3.0]-octane compounds as ERK5 inhibitors, pharmaceutical compositions, use of such compounds in treating cancer, and processes for preparing such compounds.
Li M, Fang J, Qi G
… +10 more, Guo S, Xu T, Lu Y, Yuan Q, Wang J, Zhu S, Shen J, Yang H, Xie X, Wang K
ACS Med Chem Lett
· 2026 Jun · PMID 42305200
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Orforglipron is a leading oral small-molecule glucagon-like peptide-1 receptor (GLP-1R) agonist for metabolic diseases; however, its oral exposure plateaus at higher doses, potentially limiting therapeutic efficacy. The...Orforglipron is a leading oral small-molecule glucagon-like peptide-1 receptor (GLP-1R) agonist for metabolic diseases; however, its oral exposure plateaus at higher doses, potentially limiting therapeutic efficacy. The solvent-exposed 4-fluoro-1-methylindazole branch of orforglipron was identified as a site amenable to modification for improving the physicochemical and pharmacokinetic properties. Systematic structure-activity relationship studies demonstrated that this region is highly tolerant of ring closure and expansion, yielding compounds and with subnanomolar hGLP-1R agonistic activity (EC = 0.64 and 0.53 nM, respectively). Compared with orforglipron, both compounds exhibited markedly improved permeability (Caco-2 = 2.83 and 4.75 nm/s vs 0.14 nm/s) and enhanced oral bioavailability in mice (54.0% and 72.4% vs 6.4%). , and produced robust glucose-lowering and food-intake-suppressing effects. Collectively, modification at the 4-fluoro-1-methylindazole site defines an effective strategy to enhance oral pharmacokinetics without compromising potency, providing a foundation for further optimization.