Ye Li,Wenbo Zhang,Shuwen Xue,Chaoran Zhang,Wenjing Jin,Xinru Li,Zhongxia Zhou,Li Chai,Mutian Jia,Ni Gao,Wei Wang,Xinyong Liu,Dongwei Kang
{"title":"Discovery of C5-Substituted 2′-Fluorinated Pyrimidine Nucleosides as Potent and Orally Efficacious Anti-HSV Agents","authors":"Ye Li,Wenbo Zhang,Shuwen Xue,Chaoran Zhang,Wenjing Jin,Xinru Li,Zhongxia Zhou,Li Chai,Mutian Jia,Ni Gao,Wei Wang,Xinyong Liu,Dongwei Kang","doi":"10.1021/acs.jmedchem.6c02157","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.6c02157","url":null,"abstract":"Abstract Herpes simplex virus (HSV) infections remain a significant global health concern. Through phenotypic screening of a nucleoside-focused library followed by systematic structure−activity relationship (SAR) explorations, we identified C5-substituted 2′-fluorinated pyrimidine nucleosides as promising anti-HSV scaffolds. We found that introducing five-membered heteroaryls at the uracil C5 position significantly enhanced antiviral potency, whereas cytosine and alkynyl derivatives showed limited efficacy. The optimized lead, B10, exhibited potent in vitro inhibition against HSV-1 (EC50 = 0.60 μM) and HSV-2 (EC50 = 7.32 μM) with minimal cytotoxicity. Importantly, B10 demonstrated a highly favorable oral bioavailability of 48.0% in rats. In a murine intranasal HSV-1 infection model, oral administration of B10 significantly improved survival rates, alleviated weight loss, suppressed acute viral replication in the central nervous system, and reduced pulmonary viral titers. These findings highlight the 2′-fluoro-C5-heteroaryl uracil framework as a robust chemotype and establish B10 as an orally efficacious candidate for HSV therapy.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"16 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2026-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149210257","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Ravi V. J. Chari,Chuan Shen,Susan Clardy,Nicolas Severe,Nicole Meiser,Marsha Crochiere,Balu N. Balasubramanian
{"title":"Site-Specific Bioconjugation in Antibody−Drug Conjugates: From Conjugation Chemistry to Precision Molecular Design","authors":"Ravi V. J. Chari,Chuan Shen,Susan Clardy,Nicolas Severe,Nicole Meiser,Marsha Crochiere,Balu N. Balasubramanian","doi":"10.1021/acs.jmedchem.6c02354","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.6c02354","url":null,"abstract":"","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"18 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2026-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149210251","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"A Modular Peptide Strategy for Targeted Lysosomal Degradation of TGF-βR1","authors":"Liang Qi,Daimin Luo,Wei Cheng,Qinglin Tang,Jiale Dong,Han Liu,Zhuowen Li,Yanqiu Yuan,Haonan Li,Xianxing Jiang","doi":"10.1021/acs.jmedchem.6c01441","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.6c01441","url":null,"abstract":"Abstract Direct depletion of TGF-βR1 may provide more durable suppression of profibrotic signaling than occupancy-driven inhibition, but compact lysosome-directed degraders remain underdeveloped. Here, we report a peptide-based strategy for lysosomal degradation of TGF-βR1 by re-engineering a caveolin-derived antifibrotic scaffold. Structure-guided optimization identified T19 as an improved TGF-βR1-directed sequence, and incorporation of an intrinsic lysosome-targeting module generated P2, which induced time and dose-dependent, lysosome-dependent TGF-βR1 downregulation. Fatty-acid conjugation afforded P2-FA with improved stability and pharmacokinetic properties. P2-FA suppressed profibrotic signaling, reduced α-SMA and COL1A1 expression, and inhibited proliferation and migration of activated LX-2 cells. In a CCl4-induced mouse model, P2-FA attenuated collagen deposition, decreased fibrotic marker expression, and alleviated liver injury. These results identify P2-FA as a pharmacologically improved peptide-based TGF-βR1 degrader and antifibrotic lead.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"4 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2026-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149210247","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Arina Ranjit,Lukáš Tenora,Meixiang Huang,Ying Wu,Ajit G. Thomas,Chae Bin Lee,Jesse Alt,Ruoning Zhang,Robert M. Maragakis,Yuxin Zheng,Yu Su,Peter Pietri,Taeyoon Jung,Barbara S. Slusher,Rana Rais
{"title":"Next-Generation Neutral Sphingomyelinase-2 Inhibitors with Improved Solubility, Pharmacokinetics, and Efficacy in a Tau Propagation Model","authors":"Arina Ranjit,Lukáš Tenora,Meixiang Huang,Ying Wu,Ajit G. Thomas,Chae Bin Lee,Jesse Alt,Ruoning Zhang,Robert M. Maragakis,Yuxin Zheng,Yu Su,Peter Pietri,Taeyoon Jung,Barbara S. Slusher,Rana Rais","doi":"10.1021/acs.jmedchem.6c02429","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.6c02429","url":null,"abstract":"Abstract Neutral sphingomyelinase 2 (nSMase2) is a promising therapeutic target implicated in disease progression. We previously identified PDDC [phenyl (R)-(1-(3-(3,4-dimethoxyphenyl)-2,6-dimethylimidazo[1,2-b]pyridazin-8-yl)-pyrrolidin-3-yl) carbamate], a sub-micromolar nSMase2 inhibitor with favorable efficacy and pharmacokinetics in mice. However, poor aqueous solubility and suboptimal pharmacokinetics in higher species limited its translational potential. To overcome these limitations, we introduced hydroxy groups on the southern phenyl ring and simultaneously optimized the northern phenyl-carbamate moiety. Compound 8a [(phenyl (R)-(1-(3-(4-hydroxyphenyl)-2,6-dimethylimidazo[1,2-b]pyridazin-8-yl)pyrrolidin-3-yl) carbamate] exhibited comparable potency and pharmacokinetics to PDDC but remained poorly soluble. To address this, we derivatized the hydroxy group with hydrophilic phosphate promoeities, generating soluble analogues of 8a. Of these, 12a demonstrated excellent aqueous solubility and efficiently released 8a, resulting in improved pharmacokinetics, target engagement, and efficacy in mice. In dogs, oral dosing of 12a resulted in the release of 8a, with the released 8a exhibiting 47% absolute oral bioavailability, supporting its translational potential.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"25 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2026-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149210298","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Development of a Potent and Isoform-Selective HDAC11 Inhibitor with Anti-Tumor Efficacy against Non-Small Cell Lung Cancer","authors":"Xinyu Yang,Xin Li,Rui Huang,Yanting Zhou,Hongyan Li,Pan Yao,Yue Hu,Yuhang Liu,Changning Wang,Ping Bai","doi":"10.1021/acs.jmedchem.6c01054","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.6c01054","url":null,"abstract":"Abstract Targeting histone deacetylase 11 (HDAC11) represents a promising therapeutic strategy, yet developing selective inhibitors for solid tumors remains a formidable challenge. Herein, we describe the rational lead optimization of a novel series of indole-based hydroxamic acids. Guided by our previous lead PB94, a systematic, multiparameter optimization of the core, linker, and cap regions was conducted to specifically target HDAC11. This campaign yielded compound YP200, which incorporates a precisely positioned secondary amine linker and an adamantane surface-recognition cap. YP200 exhibited exceptional HDAC11 inhibitory potency (IC50 = 0.058 ± 0.01 μM) and good selectivity (>103-fold) over other HDACs. Furthermore, YP200 demonstrated good in vivo anti-tumor efficacy in a non-small cell lung cancer (NSCLC) patient-derived xenograft model. These findings validate YP200 as a promising HDAC11-targeted therapeutic candidate, significantly expanding the therapeutic arsenal for solid tumors.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"53 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2026-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149210256","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Raymond G. Flax,Andrea Lacigová,Stefanie Howell,Haoxi Li,Frances M. Bashore,Lukáš Čajánek,Alison D. Axtman
{"title":"Potent and Cell Active 5-Azaindole-based Tau Tubulin Kinase Inhibitors Disrupt Ciliogenesis","authors":"Raymond G. Flax,Andrea Lacigová,Stefanie Howell,Haoxi Li,Frances M. Bashore,Lukáš Čajánek,Alison D. Axtman","doi":"10.1021/acs.jmedchem.6c01323","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.6c01323","url":null,"abstract":"Abstract We have characterized a potent and cell active tau tubulin kinase 1 and 2 (TTBK1 and TTBK2) inhibitor, 13. Analysis of the in-cell, kinome-wide selectivity of compound 13 revealed it to only bind five of 300 kinases with >50% occupancy at 1 μM: CDK11B, CDK11A, CK1δ, CK1ε, and EPHA2. Extensive dose−response follow-up studies in cells refined the off-target kinases of compound 13 to include CDK11B, CDK11A, CK1δ, and PIKfyve based on their NanoBRET IC50 values being <1 μM. As part of our medicinal chemistry campaign, we also identified a structurally similar negative control, compound 5, which lacks in-cell affinity for TTBK1 and TTBK2. TTBK2 is an effector of ciliogenesis, acting in concert with CEP164, CP110, and CEP83 to initiate the biogenesis of primary cilia. We demonstrate that compound 13 ablates TTBK2 autophosphorylation and significantly disrupts ciliogenesis in hTERT-RPE-1 cells, making it a powerful tool compound for ciliary studies.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"21 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2026-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149210252","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Alpha-Lipoic Acid Derivatives: A Multifunctional Neuroprotective Agent with Potential for Treating Ischemic Stroke","authors":"Jialun Zou,Feng Gao,Yilin Luo,Xinyue Bai,Yuan Ru,Wanyi Cen,Mengdi Lv,Jia Wang,Ning Zhang,Qianqian Hu,Xiaolong Liu","doi":"10.1021/acs.jmedchem.6c00739","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.6c00739","url":null,"abstract":"Abstract Ischemic stroke (IS) is a major public health burden due to its high mortality and disability rates. Neuroinflammation and ferroptosis are two key drivers of IS progression. α-Lipoic acid (ALA) exhibits both anti-ferroptosis and anti-inflammatory activities; however, its anti-ferroptosis efficacy is suboptimal. In this study, we designed and synthesized 23 ALA derivatives. Among them, D14 exhibited the most potent anti-ferroptosis activity, with an EC50 value of 0.00247 μM, an approximately 16,000-fold improvement over ALA, while retaining comparable anti-inflammatory activity (IC50 = 13.6 μM). Mechanistically, D14 scavenged free radicals and activated the Nrf2/GPX4 pathway to restore GSH levels and reduce MDA, Fe2+, and ROS accumulation, thereby inhibiting ferroptosis. D14 also suppressed NF-κB activation by preventing IκBα degradation and p65 phosphorylation, and it reduced IL-1β, IL-6, and TNF-α secretion. In a rat middle cerebral artery occlusion (MCAO) model, D14 reduced cerebral infarct volume and ameliorated neurological deficits, surpassing ALA and the clinically used drug edaravone. Preliminary toxicity evaluation of D14 indicated a favorable safety profile. Overall, D14 is a promising multi-target lead compound for the treatment of IS.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"25 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2026-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149210253","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Shubham K. Singh,Vijayarani Potluri,Surabhi Naza,Raveendra Madhukar Bhat,Poonam Patil,Hemavarshine M. S,Bhavita Kattula,Sarvalakshmi Pusarapu,Kalichamy Alagarasu,Rangappa S. Keri,Deepti Parashar,Anthony Addlagatta,Pragati K. Prasad
{"title":"Discovery of Indazole-Based Dual-Pharmacophore Inhibitors of Dengue and Zika Proteases as Promising Antivirals","authors":"Shubham K. Singh,Vijayarani Potluri,Surabhi Naza,Raveendra Madhukar Bhat,Poonam Patil,Hemavarshine M. S,Bhavita Kattula,Sarvalakshmi Pusarapu,Kalichamy Alagarasu,Rangappa S. Keri,Deepti Parashar,Anthony Addlagatta,Pragati K. Prasad","doi":"10.1021/acs.jmedchem.6c00523","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.6c00523","url":null,"abstract":"Abstract Flavivirus outbreaks caused by dengue virus (DENV) and Zika virus (ZIKV) remain a major global health challenge, with no FDA-approved antivirals available. Herein, we designed, synthesized, and evaluated indazole-based dual pharmacophore motifs targeting NS2B-NS3 serine proteases, essential for viral replication. Enzymatic assays revealed nanomolar to sub-micromolar potency, with strong selectivity over host serine proteases, minimizing off-target risks. Biophysical studies showed ligand-induced thermal stabilization, while kinetic and dialysis analyses confirmed a reversible, competitive, non-covalent inhibition mechanism. In DENV-infected Vero CCL-81 cells, several leads exhibited potent antiviral activity with low cytotoxicity. Notably, compound C8 demonstrated low-nanomolar enzyme inhibition against both viruses, translating to complete viral suppression in cells (EC50 = 0.5 μM) with a good selectivity index, underscoring its therapeutic potential. Molecular docking and molecular dynamics simulations supported these findings, revealing key active-site interactions consistent with potency and specificity. Collectively, these results highlight indazole-based dual-pharmacophore inhibitors as promising anti-flaviviral leads.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"25 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2026-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149210312","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Tao Wang,Matthew S. Dowling,Dahui Zhou,David Jonathan Wasilko,Meihua Tu,Denis Feliers,Barbara Bernardo,Joseph Tillotson,Wenzhe Ma,Janice Brown,Zachary Johnson,Joshua A. Lees,Andrew Fensome,Andre Shavnya,Jennifer Clemens,Steven Coffey,Caroline A. Blakemore,Melissa Avery,Jamison B. Tuttle,Phillip Hudson,Magdalena Korczynska,John Murray,Jade Williams,Jun Xiao,Jason Dutra,Dianne Hernandez,Kevin D. Hesp,Vincent Mascitti,Srinath Jagarlapudi,Rose Keenan,Jessica Ward,Robert Barnes,Emily Jordan,Natalie Ochocki,Daniel Callahan,Kimberly Steen,Amit S. Kalgutkar,Kari R. Fonseca,Raman Sharma,Nicholas Ferguson,Amanda King-Ahmad,Andrew J. Bessire,Amy Moody,Tristan S. Maurer,Ingrid A. Stock,Ruth Sommese,Tracy Phillips,Paula M. Loria,Huixian Wu,David Hepworth,Matthew F. Sammons,Lei Zhang,Yuan Zhang
{"title":"Structure-Guided Discovery of Orally Bioavailable Allosteric SLC6A19 Inhibitors that Promote Urinary Amino Acid Excretion In Vivo","authors":"Tao Wang,Matthew S. Dowling,Dahui Zhou,David Jonathan Wasilko,Meihua Tu,Denis Feliers,Barbara Bernardo,Joseph Tillotson,Wenzhe Ma,Janice Brown,Zachary Johnson,Joshua A. Lees,Andrew Fensome,Andre Shavnya,Jennifer Clemens,Steven Coffey,Caroline A. Blakemore,Melissa Avery,Jamison B. Tuttle,Phillip Hudson,Magdalena Korczynska,John Murray,Jade Williams,Jun Xiao,Jason Dutra,Dianne Hernandez,Kevin D. Hesp,Vincent Mascitti,Srinath Jagarlapudi,Rose Keenan,Jessica Ward,Robert Barnes,Emily Jordan,Natalie Ochocki,Daniel Callahan,Kimberly Steen,Amit S. Kalgutkar,Kari R. Fonseca,Raman Sharma,Nicholas Ferguson,Amanda King-Ahmad,Andrew J. Bessire,Amy Moody,Tristan S. Maurer,Ingrid A. Stock,Ruth Sommese,Tracy Phillips,Paula M. Loria,Huixian Wu,David Hepworth,Matthew F. Sammons,Lei Zhang,Yuan Zhang","doi":"10.1021/acs.jmedchem.6c02154","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.6c02154","url":null,"abstract":"Abstract SLC6A19 is a sodium-dependent transporter that mediates the absorption of neutral amino acids in the intestine and reabsorption of these amino acids in the kidney. Pharmacological inhibition of SLC6A19 may provide therapeutic benefit by normalizing plasma amino acid levels and potentially reducing renal tubular transport burden. Virtual screening against an allosteric binding pocket observed in the cryo-EM structure of SLC6A19/cinromide (1) identified compound 6 as a promising hit. The cryo-EM structure of SLC6A19/CB3 (2) revealed a second, partially overlapping pocket adjacent to the compound 6 binding site. Analogue design merging these two binding pockets followed by optimization led to compound 20, a potent, selective, and orally bioavailable allosteric SLC6A19 inhibitor. While compound 20 demonstrates an approximately 10-fold rightward potency shift against mouse SLC6A19, it retains good potency against non-human primate SLC6A19. Consistent with the SLC6A19 inhibition mechanism, oral dosing of 20 led to increased urinary amino acid excretion in a dose-dependent manner in human SLC6A19 knock-in mice and wild-type non-human primates.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"18 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2026-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149210296","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Ye Tao,Holly H. Guo,Victor E. Cruz,Divya Reddy,Ashley Leach,Noelle S. Williams,Arin B. Aurora,Vishal Khivansara,Yan Han,Jan P. Erzberger,Deepak Nijhawan,Jef K. De Brabander
{"title":"Discovery and Optimization of Anticancer Dibenzothiazepinones That Target the Ribosome Biogenesis Factor NVL","authors":"Ye Tao,Holly H. Guo,Victor E. Cruz,Divya Reddy,Ashley Leach,Noelle S. Williams,Arin B. Aurora,Vishal Khivansara,Yan Han,Jan P. Erzberger,Deepak Nijhawan,Jef K. De Brabander","doi":"10.1021/acs.jmedchem.6c02184","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.6c02184","url":null,"abstract":"Abstract Using inducible forward genetics, we recently discovered a dibenzothiazepinone (1) with activity against cancer cells via inhibition of the ribosome biogenesis factor NVL (nuclear valosin-containing protein-like). Herein, we delineate a comprehensive structure−activity relationship (SAR) study that explores the structural space surrounding the dibenzothiazepinone scaffold. A series of 115 analogs were synthesized and evaluated for activity against the colorectal cancer cell line HCT116 and counter-screened against cells CRISPR engineered to express a compound-resistant mutation in NVL. Our initial medicinal chemistry-driven campaign focused on improving potency, metabolic stability, and in vivo exposure and clearance. A fluorescence polarization assay with recombinant human NVL established a correlation between NVL-binding and antiproliferative activity. Cryo-EM structures of human NVL with select inhibitors revealed a binding mode that is consistent with the SAR data. This study led to the in vivo analog 100 (MM927), which we reported to suppress tumor growth in vivo without detectable toxicity via targeting the NVL.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"12 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2026-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149210299","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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