Shota Kikuchi, Jason C. Green, Don C. Rogness, Betty Lam, Zachary A. Owyang, Robert D. Malmstrom, Ali Tabatabaei, Aaron N. Snead, Melissa A. Hoffman, Steffen M. Bernard, Paige Ashby, Kelsey N. Lamb, Benjamin D. Horning, Kristen A. Baltgalvis, Kent T. Symons, Thomas A. Glaza, Chu-Chiao Wu, Xiaodan Song, Martha K. Pastuszka, John J. Sigler, Jonathan Pollock, Laurence Burgess, Gabriel M. Simon, Matthew P. Patricelli, David S. Weinstein
{"title":"Identification of VVD-214/RO7589831, a Clinical-Stage, Covalent Allosteric Inhibitor of WRN Helicase for the Treatment of MSI-High Cancers","authors":"Shota Kikuchi, Jason C. Green, Don C. Rogness, Betty Lam, Zachary A. Owyang, Robert D. Malmstrom, Ali Tabatabaei, Aaron N. Snead, Melissa A. Hoffman, Steffen M. Bernard, Paige Ashby, Kelsey N. Lamb, Benjamin D. Horning, Kristen A. Baltgalvis, Kent T. Symons, Thomas A. Glaza, Chu-Chiao Wu, Xiaodan Song, Martha K. Pastuszka, John J. Sigler, Jonathan Pollock, Laurence Burgess, Gabriel M. Simon, Matthew P. Patricelli, David S. Weinstein","doi":"10.1021/acs.jmedchem.5c01805","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.5c01805","url":null,"abstract":"Werner syndrome helicase (WRN) has emerged as a compelling therapeutic target for microsatellite instability-high (MSI-H) cancers, owing to its selective dependency on the helicase activity of WRN. Despite the inherent challenges in targeting helicases, our chemoproteomics approach enabled the identification of compounds that covalently engage C727 within an allosteric pocket of WRN, thereby inhibiting its ability to unwind DNA. Through optimization of each molecular component, particularly focusing on the vinyl sulfone warhead and C2 substitution at the pyrimidine core, an optimal balance of intrinsic reactivity, inhibitory potency, and metabolic stability was achieved, culminating in the identification of VVD-214/RO7589831. This process underscored the tunability of the vinyl sulfone warhead and its effectiveness in covalent drug discovery. VVD-214 induced tumor regression in MSI-H colorectal cancer models and is being evaluated as a promising therapeutic candidate for MSI-H cancers.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"49 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2025-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145077932","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}
Fatemeh Sarmadi,Amelia Caza,Zhizhong Gao,Natacha Rochel,James L Gleason,John H White
{"title":"Hyperagonism of a Vitamin D Receptor Agonist/Histone Deacetylase Inhibitor Hybrid Molecule.","authors":"Fatemeh Sarmadi,Amelia Caza,Zhizhong Gao,Natacha Rochel,James L Gleason,John H White","doi":"10.1021/acs.jmedchem.5c01932","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.5c01932","url":null,"abstract":"1,25-Dihydroxyvitamin D (1,25D) analogs engage the vitamin D receptor (VDR) and can exert anticancer and immunomodulatory effects. Although tumors often resist 1,25D monotherapy, combining VDR agonism with histone deacetylase inhibitors (HDACi) restores anticancer efficacy. Here, we present AC-340, a novel bifunctional molecule that incorporates HDACi into a VDR agonist backbone. Besides its robust bifunctionality in vitro in multiple melanoma models, RNaseq analysis of B16-F10 mouse melanoma cells revealed that AC-340 superinduces the expression of a broad array of VDR target genes. Comparative structural studies and ChIP-qPCR revealed that AC-340 forms more interactions than 1,25D with residues in the VDR coactivator binding domain, leading to more efficacious recruitment of coactivator CBP. This, likely coupled with AC-340 HDACi activity, leads to elevated H3K27 acetylation of VDR target genes, a mark of active transcription. Thus, AC-340 functions as a VDR hyperagonist and should be efficacious in mono- or combination therapies against multiple cancer models.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"16 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2025-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145083411","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}
Xiangkai Ji,Xiangyi Jiang,Zhen Gao,Heng Gao,Xing Huang,Fabao Zhao,Erik De Clercq,Zhao Wang,Christophe Pannecouque,Dongwei Kang,Peng Zhan,Xinyong Liu
{"title":"Exploring the HIV-1 Reverse Transcriptase p51/p66 Interface: Structure-Based Design and Optimization of Novel 2,4,6-Trisubstituted Pyrimidines as Potent NNRTIs with Improved Resistance Profiles.","authors":"Xiangkai Ji,Xiangyi Jiang,Zhen Gao,Heng Gao,Xing Huang,Fabao Zhao,Erik De Clercq,Zhao Wang,Christophe Pannecouque,Dongwei Kang,Peng Zhan,Xinyong Liu","doi":"10.1021/acs.jmedchem.5c01695","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.5c01695","url":null,"abstract":"The emerging challenge of HIV-1 drug resistance urgently demands the development of next-generation HIV-1 non-nucleoside reverse transcriptase inhibitors (NNRTIs). Herein, we designed and synthesized two series of novel 2,4,6-trisubstituted pyrimidines that target a previously insufficiently explored binding site at the interface between the p66 and p51 subunits of HIV-1 reverse transcriptase (RT). After iterative structural optimization, 15k turned out to exhibit potent antiviral activity to wild-type and mutant HIV-1 strains, with EC50 values ranging from 0.0046 to 0.033 μM and relatively low cytotoxicity (CC50 = 26.64 μM). Molecular modeling revealed that 15k adopts a unique \"Y-shaped\" conformation within the NNRTI-binding pocket (NNIBP), forming novel hydrogen bonds with E138 and K101 at the p51-p66 interface─a key factor contributing to its potent resistance profile. Moreover, 15k exhibits favorable in vivo metabolic (T1/2 = 2.12 h) and safety profiles. In summary, newly discovered 15k represents a promising anti-HIV-1 drug candidate for further development.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"17 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2025-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145071846","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}
Morgane Mannes, , , Dora Mugoli Chigoho, , , Charlotte Martin, , , Thomas Barlow, , , Tine Hectors, , , Tom Govaerts, , , Pieterjan Kayaert, , , Kirsten De Ridder, , , Carole Delachaume, , , Béatrice Vayssière, , , Martin Andrews*, , , Sophie Hernot*, , and , Steven Ballet*,
{"title":"Targeted Delivery of Oligonucleotide–Peptide Conjugates for Enhanced Kidney-Specific Therapy","authors":"Morgane Mannes, , , Dora Mugoli Chigoho, , , Charlotte Martin, , , Thomas Barlow, , , Tine Hectors, , , Tom Govaerts, , , Pieterjan Kayaert, , , Kirsten De Ridder, , , Carole Delachaume, , , Béatrice Vayssière, , , Martin Andrews*, , , Sophie Hernot*, , and , Steven Ballet*, ","doi":"10.1021/acs.jmedchem.5c01893","DOIUrl":"10.1021/acs.jmedchem.5c01893","url":null,"abstract":"<p >Targeted drug delivery has emerged as a crucial strategy to enhance efficacy and minimize side effects from off-target interactions, a particularly relevant approach for kidney diseases, where many treatments suffer from poor targeting efficiency. In this study, we benchmarked a series of peptides previously identified for their kidney-targeting potential, utilizing them as targeting moieties for an oligonucleotide aimed at repressing HIF-1α expression in renal tubular cells. The peptides were synthesized, radiolabeled, and evaluated for their biodistribution profiles in mice. The best-performing peptide was conjugated to the oligonucleotide of interest, leveraging its kidney-targeting properties to optimize the delivery. We demonstrated that conjugation of the oligonucleotide to a kidney-targeting peptide preserved its repressing HIF-1α activity, while increasing accumulation 10-fold in the kidneys. The results from this study offer valuable insights into the potential of kidney-targeting peptides as a novel strategy to improve the efficacy and safety of therapies for kidney diseases.</p>","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"68 18","pages":"19584–19597"},"PeriodicalIF":6.8,"publicationDate":"2025-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145071845","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}
Shuaiqi Feng,Yan Chen,Zhifang Liu,Shilei Ji,Qingpeng Wang
{"title":"Development of Ciprofibrate Platinum(IV) Nanodrugs as Antimetastatic Agents with COFs as Carriers.","authors":"Shuaiqi Feng,Yan Chen,Zhifang Liu,Shilei Ji,Qingpeng Wang","doi":"10.1021/acs.jmedchem.5c01395","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.5c01395","url":null,"abstract":"Dysregulated cholesterol accumulation promotes tumor growth and metastasis. Herein, a series of ciprofibrate platinum(IV) conjugates with cholesterol-inhibiting effects was developed, and the transferrin-modified nanodrug Tf-PEG-COFs@Pt(IV) was prepared using COFs as the carrier. The nanodrug exhibited potent antiproliferative and antimetastatic activities both in vitro and in vivo. The transferrin moiety significantly enhanced the tumor-targeting ability of the nanodrug. The platinum core induced serious DNA damage, leading to an increased expression of γ-H2AX and p53. Mitochondria-mediated apoptosis occurred via the Bcl-2/Bax/caspase-3 cascade. Notably, cholesterol accumulation was inhibited by the ciprofibrate ligand through promoting PPAR-α expression and further regulating the LDLR/ACAT1/ABCA1 signaling. The nanodrug effectively reversed the epithelial-mesenchymal transition by inhibiting the PI3K/AKT/mTOR pathway and reversing the hypoxic microenvironment. Furthermore, antitumor immunity was enhanced by elevating the density of CD3+ and CD8+ T cells and triggering macrophage polarization from the M2 to M1 phenotype in tumors.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"38 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2025-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145071848","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}
Sam E. Mann, Julien Lefranc, Omar Alkhatib, Roch Boivin, Jörg Bomke, Robert T. Byrne, Carolina P. Cassona, Xiaoling Chen, Irina Cornaciu, Paula Costales, Owen A. Davis, Lizbeth DeSelm, Elias Elinati, Bruce Follows, Alessandro Galbiati, Christoph Göldner, Jasvinder K. Hayre, Catherine Jorand-Lebrun, Claudio A. Lademann, Birgitta Leuthner, Jayesh B. Majithiya, Catarina F. Malta, Bethany Mason, Claire L. McWhirter, Bernd Neff, J. Willem M. Nissink, Ulrich Pehl, Carl Petersson, Andrea Pica, Maria Filipa Pinto, Eeson Rajendra, Christin Rakers, Ana Toste Rêgo, Helen M. R. Robinson, Ada Sala-Hojman, Theresia A. Schaedler, Paul J. L. Schürmann, Diana O. Silva, Graeme C. M. Smith, Fiona Sorrell, Gina R. Webster, Frank T. Zenke, Robert A. Heald, Lars T. Burgdorf
{"title":"Fragment-Based Discovery and Structure-Led Optimization of MSC778, the First Potent, Selective, and Orally Bioavailable FEN1 Inhibitor","authors":"Sam E. Mann, Julien Lefranc, Omar Alkhatib, Roch Boivin, Jörg Bomke, Robert T. Byrne, Carolina P. Cassona, Xiaoling Chen, Irina Cornaciu, Paula Costales, Owen A. Davis, Lizbeth DeSelm, Elias Elinati, Bruce Follows, Alessandro Galbiati, Christoph Göldner, Jasvinder K. Hayre, Catherine Jorand-Lebrun, Claudio A. Lademann, Birgitta Leuthner, Jayesh B. Majithiya, Catarina F. Malta, Bethany Mason, Claire L. McWhirter, Bernd Neff, J. Willem M. Nissink, Ulrich Pehl, Carl Petersson, Andrea Pica, Maria Filipa Pinto, Eeson Rajendra, Christin Rakers, Ana Toste Rêgo, Helen M. R. Robinson, Ada Sala-Hojman, Theresia A. Schaedler, Paul J. L. Schürmann, Diana O. Silva, Graeme C. M. Smith, Fiona Sorrell, Gina R. Webster, Frank T. Zenke, Robert A. Heald, Lars T. Burgdorf","doi":"10.1021/acs.jmedchem.5c01526","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.5c01526","url":null,"abstract":"Flap endonuclease 1 (FEN1) is a long-standing target of interest in the DNA damage response (DDR) field due to its therapeutic potential in <i>BRCA</i> mutant cancers. To-date there have only been a handful of FEN1 inhibitors reported in the literature, most of which display modest selectivity and/or weak cellular activity. As such, there is a need for more advanced pharmacological tools to probe the biology of FEN1. Here, we report the discovery of <b>MSC778</b>, the first potent, selective, and orally bioavailable FEN1 inhibitor. We describe our metal-chelating fragment screening approach and structure-based optimization to identify <b>MSC778</b>, using structural insights to drive design. Consistent with FEN1 inhibition, <b>MSC778</b> selectively kills <i>BRCA2</i>-deficient cells and potentiates the activity of PARPi niraparib <i>in vivo</i> to induce tumor stasis in a <i>BRCA2</i> KO DLD-1 mouse xenograft. Furthermore, we illustrate how development of this approach has the potential for addressing nucleases as a target class.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"73 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2025-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145077880","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":"Strategic Design of Triple GLP-1R/GCGR/GIPR Agonists with Varied Receptor Potency: Achieving Comparable Glycemic and Weight Reduction Effects.","authors":"Shuang Wang,Yun Liu,Zhiming Yan,Xianxian Huang,Yonghe Liao,Chunli Tang,Lin Jing,Zhongbo Zhou,Jing Han,Weizhong Tang,Neng Jiang","doi":"10.1021/acs.jmedchem.5c02032","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.5c02032","url":null,"abstract":"Triple activation of the glucagon-like peptide 1 receptor (GLP-1R), the GIP receptor (GIPR), and the glucagon receptor (GCGR) is an innovative strategy for treating obesity and diabetes. We report the rational design of triple GLP-1R/GCGR/GIPR agonists, featuring potent GLP-1R and GCGR activity with weaker GIPR activation. Using sequence analysis, molecular dynamics simulations, docking, and amino acid optimization, we developed xGLP-1-based triagonists, with xGLP/GCG/GIP-32 exhibiting a unique activation profile. It shows superior weight loss effects compared to tirzepatide and similar metabolic efficacy to retatrutide, despite significantly less potent GIPR activity. Preliminary mechanistic studies revealed that xGLP/GCG/GIP-32 exhibits biased agonism toward the GIPR and GCGR. These activity data suggest it may not be imperative to focus solely on potent activation of all three receptors. Especially for triple agonists with receptor-biased agonism, there may be room to explore optimal receptor activation ratios.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"71 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2025-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145071849","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":"Discovery, Optimization, and Evaluation of Novel ANGPTL3 Modulators for the Treatment of Hyperlipidemia","authors":"Shurui Zhang, , , Jing Zhao, , , Xiong Xie, , , Luhan Li, , , Jiayi Chen, , , Hong Liu*, , and , Jiang Wang*, ","doi":"10.1021/acs.jmedchem.5c00732","DOIUrl":"10.1021/acs.jmedchem.5c00732","url":null,"abstract":"<p >Angiopoietin-like protein 3 (ANGPTL3) has emerged as an attractive therapeutic target for treating hyperlipidemia. Evinacumab, a monoclonal antibody targeting ANGPTL3, was approved by the FDA for homozygous familial hypercholesterolemia in 2021. Here, a series of novel sulfonamide scaffold ANGPTL3 modulators were designed and synthesized based on the structure–activity relationship (SAR) analysis. Among them, compound <b>20</b> exhibited potent inhibition of <i>ANGPTL3</i> gene expression with an IC<sub>50</sub> value of 0.22 μM, reduced both <i>ANGPTL3</i> mRNA and protein levels, and significantly enhanced lipoprotein lipase (LPL) activity. More importantly, compound <b>20</b> remarkably lowered serum levels of triglycerides (TG), total cholesterol, and LDL cholesterol (LDL-C) in high-fat-diet-induced hyperlipidemic models, with favorable pharmacokinetic properties and safety profiles. Collectively, a novel ANGPTL3 small-molecule modulator compound <b>20</b> with a distinct core structure was first reported, offering potential for therapeutic development in hyperlipidemia.</p>","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"68 18","pages":"18930–18948"},"PeriodicalIF":6.8,"publicationDate":"2025-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145068294","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}
Ke Kong, , , Wei Zhao, , , Jonathan H. Shrimp, , , Marius Vava, , , Rohan Sinha, , , Shweta Sharma, , , Tobie D. Lee, , , Jacob S. Roth, , , Olivia W. Lee, , , Devin Lewis, , , Sara E. Kearney, , , Jason M. Rohde, , , Mindy I. Davis, , , Pranav Shah, , , Amy Q. Wang, , , Xin Xu, , , Lei Shi, , , Min Shen, , , Matthew B. Boxer, , , Nabeel Bardeesy, , , Matthew D. Hall, , and , Samarjit Patnaik*,
{"title":"SAR Studies around the SULT1A1-Activated Alkylator YC-1 as Cytotoxic Agents against Biliary Tract Cancer Cells","authors":"Ke Kong, , , Wei Zhao, , , Jonathan H. Shrimp, , , Marius Vava, , , Rohan Sinha, , , Shweta Sharma, , , Tobie D. Lee, , , Jacob S. Roth, , , Olivia W. Lee, , , Devin Lewis, , , Sara E. Kearney, , , Jason M. Rohde, , , Mindy I. Davis, , , Pranav Shah, , , Amy Q. Wang, , , Xin Xu, , , Lei Shi, , , Min Shen, , , Matthew B. Boxer, , , Nabeel Bardeesy, , , Matthew D. Hall, , and , Samarjit Patnaik*, ","doi":"10.1021/acs.jmedchem.5c00489","DOIUrl":"10.1021/acs.jmedchem.5c00489","url":null,"abstract":"<p >A quantitative high-throughput screen using biliary tract cancer cell lines had identified the small-molecule YC-1 as being selectively cytotoxic against the IDH1-mutant cell lines with high expression of SULT1A1. We discuss the structure–activity relationship study of YC-1 analogs and identify the key structural motifs that are essential for this cytotoxicity. We highlight the narrow SAR around the furfuryl alcohol that has been reported as a critical motif that is activated to a reactive electrophile by the sulfotransferase enzyme SULT1A1. Drug-like properties of key analogs are evaluated, including a close look at YC1 hepatic metabolism. We also show the SAR of a smaller subset of 2-choloro-4-amino benzyl alcohols from the NCI compound collection with a similar benzyl alcohol motif. We also demonstrate the ability of key analogs to act as substrates of SULT1A1 in a colorimetric biochemical assay.</p>","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"68 18","pages":"18885–18907"},"PeriodicalIF":6.8,"publicationDate":"2025-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145068296","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":"Synthesis, Structure–Activity Relationships, and Antitumor Activities of Quinoxiline-Containing Inhibitors of the Protein–Protein Interactions between Transcription Coactivator AF9/ENL and DOT1L/AF4","authors":"Chandra Bhushan Mishra, , , Xin Li, , , Bala Krishna Moku, , , Sehun Kwak, , , Dnyaneshwar N. Garad, , and , Yongcheng Song*, ","doi":"10.1021/acs.jmedchem.5c01587","DOIUrl":"10.1021/acs.jmedchem.5c01587","url":null,"abstract":"<p >Mixed lineage leukemia (MLL) gene rearrangements cause ∼75% of acute leukemia in infants and 5–10% in children and adults with poor clinical outcomes. Protein–protein interactions (PPI) between frequent MLL fusion partners AF9/ENL and AF4 or histone methyltransferase DOT1L are drug targets for MLL-rearranged (MLL-r) leukemia. Sixty-seven quinoxiline compounds were synthesized and tested for their ability to inhibit such PPIs. Compounds <b>16</b>, <b>17</b>, <b>59</b>, and <b>63</b> were found to be potent inhibitors with IC<sub>50</sub> values of 0.35–1.5 μM. Structure–activity relationships are discussed. Potent inhibitors can suppress the expression of MLL target genes Myc and Meis1 and selectively block the proliferation of MLL-r and several other leukemia cells with EC<sub>50</sub> values as low as 0.84 μM. Compound <b>17</b> exhibited significant antitumor activities in a mouse model of MLL-r leukemia without overt toxicities. It also showed favorable pharmacokinetics in mice. These results indicate that compound <b>17</b> is a promising pharmaceutical lead for the treatment of MLL-r leukemia.</p>","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"68 18","pages":"19396–19414"},"PeriodicalIF":6.8,"publicationDate":"2025-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145068577","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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