Pub Date : 2025-04-17DOI: 10.1021/acs.jmedchem.5c00214
Petar Iliev, Conall McCutcheon, Tizita H. Admas, Anja Reithmeier, Melanie Lopez McDonald, Alexandre van Outryve, Danielle Hanke, Jennifer I. Brown, Martin Haraldsson, Robert-Alain Toillon, David A. Frank, Brent D. G. Page
Signal transducer and activator of transcription 3 (STAT3) is a promising yet challenging anticancer drug target due to its complex signaling and limited “druggability”. To this end, we herein highlight a target engagement-focused screening and optimization pipeline pursuing the discovery of novel STAT3 inhibitors. From a STAT3 differential scanning fluorimetry high-throughput screen, we identified compounds that appeared to stabilize STAT3 toward thermal aggregation and moderately inhibited cellular STAT3 activity. Subsequent evaluation using complementary and orthogonal assays revealed their high affinity for tropomyosin receptor kinase A (TrkA). Applying a similar target engagement-inspired approach, we refined inhibitor binding and selectivity toward TrkA, showing efficacy in cellular TrkA cancer models. Top compound, PI-15, demonstrated successful target engagement in a cellular thermal shift assay and potently inhibited TrkA activity in cancer cells. These approaches highlight the importance of prioritizing rigorous target engagement validation early in the drug discovery pipeline, resulting in promising new inhibitors.
{"title":"Challenging the “Undruggable”─Targeting STAT3 but Identifying Potent TrkA-Targeted Inhibitors","authors":"Petar Iliev, Conall McCutcheon, Tizita H. Admas, Anja Reithmeier, Melanie Lopez McDonald, Alexandre van Outryve, Danielle Hanke, Jennifer I. Brown, Martin Haraldsson, Robert-Alain Toillon, David A. Frank, Brent D. G. Page","doi":"10.1021/acs.jmedchem.5c00214","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.5c00214","url":null,"abstract":"Signal transducer and activator of transcription 3 (STAT3) is a promising yet challenging anticancer drug target due to its complex signaling and limited “druggability”. To this end, we herein highlight a target engagement-focused screening and optimization pipeline pursuing the discovery of novel STAT3 inhibitors. From a STAT3 differential scanning fluorimetry high-throughput screen, we identified compounds that appeared to stabilize STAT3 toward thermal aggregation and moderately inhibited cellular STAT3 activity. Subsequent evaluation using complementary and orthogonal assays revealed their high affinity for tropomyosin receptor kinase A (TrkA). Applying a similar target engagement-inspired approach, we refined inhibitor binding and selectivity toward TrkA, showing efficacy in cellular TrkA cancer models. Top compound, <b>PI-15</b>, demonstrated successful target engagement in a cellular thermal shift assay and potently inhibited TrkA activity in cancer cells. These approaches highlight the importance of prioritizing rigorous target engagement validation early in the drug discovery pipeline, resulting in promising new inhibitors.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"35 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2025-04-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143846589","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}
Pub Date : 2025-04-17DOI: 10.1021/acs.jmedchem.5c00395
Anthony K. Edmonds, Dimitrios-Ilias Balourdas, Graham P. Marsh, Robert Felix, Bradley Brasher, Jeff Cooper, Cari Graber-Feesl, Madhu Kollareddy, Karim Malik, Helen Stewart, Timothy J. T. Chevassut, Ella Lineham, Simon Morley, Oleg Fedorov, James Bennett, Mohan B. Rajasekaran, Samuel Ojeda, Drew A. Harrison, Christopher J. Ott, Andreas C. Joerger, Hannah J. Maple, John Spencer
Degraders with dual activity against BRD4 and CBP/EP300 were designed. A structure-guided design approach was taken to assess and test potential exit vectors on the dual BRD4 and CBP/EP300 inhibitor, ISOX-DUAL. Candidate degrader panels revealed that VHL-recruiting moieties could mediate dose-responsive ubiquitination of BRD4. A panel of CRBN-recruiting thalidomide-based degraders was unable to induce ubiquitination or degradation of target proteins. High-resolution protein cocrystal structures revealed an unexpected interaction between the thalidomide moiety and Trp81 on the first bromodomain of BRD4. The inability to form a ternary complex provides a potential rationale for the lack of degrader activity with these compounds, some of which have remarkable affinities close to those of (+)-JQ1, as low as 65 nM in a biochemical assay, vs 1.5 μM for their POI ligand, ISOX-DUAL. Such a “degrader collapse” may represent an under-reported mechanism by which some putative degrader molecules are inactive with respect to target protein degradation.
{"title":"Structure-Guided Design of ISOX-DUAL-Based Degraders Targeting BRD4 and CBP/EP300: A Case of Degrader Collapse","authors":"Anthony K. Edmonds, Dimitrios-Ilias Balourdas, Graham P. Marsh, Robert Felix, Bradley Brasher, Jeff Cooper, Cari Graber-Feesl, Madhu Kollareddy, Karim Malik, Helen Stewart, Timothy J. T. Chevassut, Ella Lineham, Simon Morley, Oleg Fedorov, James Bennett, Mohan B. Rajasekaran, Samuel Ojeda, Drew A. Harrison, Christopher J. Ott, Andreas C. Joerger, Hannah J. Maple, John Spencer","doi":"10.1021/acs.jmedchem.5c00395","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.5c00395","url":null,"abstract":"Degraders with dual activity against BRD4 and CBP/EP300 were designed. A structure-guided design approach was taken to assess and test potential exit vectors on the dual BRD4 and CBP/EP300 inhibitor, ISOX-DUAL. Candidate degrader panels revealed that VHL-recruiting moieties could mediate dose-responsive ubiquitination of BRD4. A panel of CRBN-recruiting thalidomide-based degraders was unable to induce ubiquitination or degradation of target proteins. High-resolution protein cocrystal structures revealed an unexpected interaction between the thalidomide moiety and Trp81 on the first bromodomain of BRD4. The inability to form a ternary complex provides a potential rationale for the lack of degrader activity with these compounds, some of which have remarkable affinities close to those of (+)-JQ1, as low as 65 nM in a biochemical assay, vs 1.5 μM for their POI ligand, ISOX-DUAL. Such a “degrader collapse” may represent an under-reported mechanism by which some putative degrader molecules are inactive with respect to target protein degradation.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"35 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2025-04-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143841216","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}
Pub Date : 2025-04-17DOI: 10.1021/acs.jmedchem.5c00152
Christoffer V. Heidtmann, Christian Ding Fisker, Sarah Løgstrup, Patrick G. Eriksen, Louise H. Storm, Kristian Stærk, Laust Moesgaard, Maria Pedersen, Martin J. Madsen, Ahmed Yusuf, Krista Urup, Iben S. Højgaard, Jayappragash Ramesh, Rasmus H. Pihlsbech, Caroline B. Sørensen, Tore L. Rønn, Alexander B. Larsen, Laurits R. Caspersen, Mathias Æ. Møller, Chris R. Sixhøj, Niels Frimodt-Møller, Janne K. Klitgaard, Thomas E. Andersen, Carsten U. Nielsen, Poul Nielsen
Based on hit 6, a triaromatic pleuromutilin (TAP) and potent bacterial protein synthesis inhibitor, we explored the chemical space surrounding its pharmacophore by synthesizing 45 new conjugates. Herein, the adenine head was exchanged for new heterocycles, and the benzyl linker exchanged for aniline-, ether-, amide-, and hydroxybenzyl linkages, with all of them successfully engaging the pharmacophore, a result which was mirrored in a strict 3D pharmacophore model. The aniline- and amide-linked conjugates moreover demonstrated greater stability in liver microsomes, while especially conjugate 21, but also 31, 43, 45, and 55 displayed excellent potency, with MRSA activities on par with 6 or better. Docking to the ribosome suggested a shifted engagement with C2469 for 21 over 6, resulting in greater multivalency, while 43/45 likely coordinates Mg2+. Lastly, conjugate 21 displayed efficacy equal to commercial Fucidin LEO (5) in a mouse Staphylococcus aureus skin infection model, highlighting its potential as a topical antibiotic lead.
{"title":"Linker and Head-Group Exploration of Anti-MRSA Triaromatic Pleuromutilins","authors":"Christoffer V. Heidtmann, Christian Ding Fisker, Sarah Løgstrup, Patrick G. Eriksen, Louise H. Storm, Kristian Stærk, Laust Moesgaard, Maria Pedersen, Martin J. Madsen, Ahmed Yusuf, Krista Urup, Iben S. Højgaard, Jayappragash Ramesh, Rasmus H. Pihlsbech, Caroline B. Sørensen, Tore L. Rønn, Alexander B. Larsen, Laurits R. Caspersen, Mathias Æ. Møller, Chris R. Sixhøj, Niels Frimodt-Møller, Janne K. Klitgaard, Thomas E. Andersen, Carsten U. Nielsen, Poul Nielsen","doi":"10.1021/acs.jmedchem.5c00152","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.5c00152","url":null,"abstract":"Based on hit <b>6</b>, a triaromatic pleuromutilin (TAP) and potent bacterial protein synthesis inhibitor, we explored the chemical space surrounding its pharmacophore by synthesizing 45 new conjugates. Herein, the adenine head was exchanged for new heterocycles, and the benzyl linker exchanged for aniline-, ether-, amide-, and hydroxybenzyl linkages, with all of them successfully engaging the pharmacophore, a result which was mirrored in a strict 3D pharmacophore model. The aniline- and amide-linked conjugates moreover demonstrated greater stability in liver microsomes, while especially conjugate <b>21</b>, but also <b>31</b>, <b>43</b>, <b>45</b>, and <b>55</b> displayed excellent potency, with MRSA activities on par with <b>6</b> or better. Docking to the ribosome suggested a shifted engagement with C2469 for <b>21</b> over <b>6</b>, resulting in greater multivalency, while <b>43</b>/<b>45</b> likely coordinates Mg<sup>2+</sup>. Lastly, conjugate <b>21</b> displayed efficacy equal to commercial Fucidin LEO (<b>5</b>) in a mouse <i>Staphylococcus aureus</i> skin infection model, highlighting its potential as a topical antibiotic lead.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"3 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2025-04-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143841215","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}
Pub Date : 2025-04-16DOI: 10.1021/acs.jmedchem.5c0039010.1021/acs.jmedchem.5c00390
Olaf Kinzel*, Steven D. Goldberg*, Maxwell D. Cummings, Christian Gege, Christoph Steeneck, Xiaohua Xue, Michael Albers, Thomas Schlüter, Gerald Kleymann, Brian Scott, Kia Sepassi, Freddy Schoetens, Hariharan Venkatesan, Virginia M. Tanis, Kevin Coe, Zachary S. Sales, John Spurlino, Cynthia Milligan, Anne M. Fourie, James P. Edwards and Thomas Hoffmann,
The retinoic acid receptor-related orphan receptor gamma t (RORγt) is a nuclear transcription factor expressed in both innate and adaptive immune cells, driving Th17 cell differentiation and IL-17 production. The IL-23/IL-17 pathway is implicated in autoimmune and inflammatory diseases, and biologics that target IL-23/IL-17 signaling are efficacious in the treatment of psoriasis and psoriatic arthritis. RORγt, at the core of this pathway, represents an attractive opportunity for small-molecule intervention; however, combining high potency, nuclear receptor selectivity, and good physicochemical properties remains a challenge for RORγt inverse agonists. Recently, thiazole amides have been identified as potent RORγt inverse agonists; however, they often suffer from CYP450 autoinduction in the rat, precluding further development. Herein, we describe the discovery and development of potent and selective thiazole bisamide RORγt inverse agonists that avoid autoinduction in the rat. This effort culminated in the discovery of JNJ-61803534, which advanced into phase 1 clinical trials.
{"title":"Identification of JNJ-61803534, a RORγt Inverse Agonist for the Treatment of Psoriasis","authors":"Olaf Kinzel*, Steven D. Goldberg*, Maxwell D. Cummings, Christian Gege, Christoph Steeneck, Xiaohua Xue, Michael Albers, Thomas Schlüter, Gerald Kleymann, Brian Scott, Kia Sepassi, Freddy Schoetens, Hariharan Venkatesan, Virginia M. Tanis, Kevin Coe, Zachary S. Sales, John Spurlino, Cynthia Milligan, Anne M. Fourie, James P. Edwards and Thomas Hoffmann, ","doi":"10.1021/acs.jmedchem.5c0039010.1021/acs.jmedchem.5c00390","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.5c00390https://doi.org/10.1021/acs.jmedchem.5c00390","url":null,"abstract":"<p >The retinoic acid receptor-related orphan receptor gamma t (RORγt) is a nuclear transcription factor expressed in both innate and adaptive immune cells, driving Th17 cell differentiation and IL-17 production. The IL-23/IL-17 pathway is implicated in autoimmune and inflammatory diseases, and biologics that target IL-23/IL-17 signaling are efficacious in the treatment of psoriasis and psoriatic arthritis. RORγt, at the core of this pathway, represents an attractive opportunity for small-molecule intervention; however, combining high potency, nuclear receptor selectivity, and good physicochemical properties remains a challenge for RORγt inverse agonists. Recently, thiazole amides have been identified as potent RORγt inverse agonists; however, they often suffer from CYP450 autoinduction in the rat, precluding further development. Herein, we describe the discovery and development of potent and selective thiazole bisamide RORγt inverse agonists that avoid autoinduction in the rat. This effort culminated in the discovery of JNJ-61803534, which advanced into phase 1 clinical trials.</p>","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"68 8","pages":"8713–8728 8713–8728"},"PeriodicalIF":6.8,"publicationDate":"2025-04-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143863238","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}
Pub Date : 2025-04-16DOI: 10.1021/acs.jmedchem.5c0052610.1021/acs.jmedchem.5c00526
Mohamed A. Zeidan, Mahmoud Abdelrahman Alkabbani, Simone Giovannuzzi, Eman F. Khaleel, Anwar A. El-Hamaky, Nourhan A. Khattab, Rehab Badi, Abdelhameed Abubakr, Abdallah M. Hamdy, Mohamed Fares, Haytham O. Tawfik*, Claudiu T. Supuran*, Wagdy M. Eldehna* and Moataz A. Shaldam,
This study investigates new anticonvulsant substances that target the epilepsy-associated carbonic anhydrase isoforms II and VII. The 1,2,3-triazole with a benzenesulfonamide motif is present in the produced molecules. Of these, 5b and 5c exhibited remarkable selectivity and inhibitory efficacy toward hCA VII and hCA II over hCA I. The KI values of 5b and 5c were 6.3 and 10.1 nM, respectively, and 21.6 and 18.9 nM, respectively. In a pilocarpine-induced paradigm, in vivo assessments showed decreased seizure severity and susceptibility with delayed seizure onset and diminished intensity. The quick absorption and in vivo stability of 5b were demonstrated by pharmacokinetic investigations. Evaluations of toxicity showed no neurotoxic effects and a high safety margin (LD50 > 2000 mg/kg). Mechanistic research has shown effectiveness in maintaining neuronal integrity, reducing mTOR activation, and raising hippocampus KCC2 levels. Compound 5b’s binding interactions with hCA II and hCA VII were clarified by docking and dynamics experiments.
{"title":"Shooting an Arrow against Convulsion: Novel Triazole-Grafted Benzenesulfonamide Derivatives as Carbonic Anhydrase II and VII Inhibitors","authors":"Mohamed A. Zeidan, Mahmoud Abdelrahman Alkabbani, Simone Giovannuzzi, Eman F. Khaleel, Anwar A. El-Hamaky, Nourhan A. Khattab, Rehab Badi, Abdelhameed Abubakr, Abdallah M. Hamdy, Mohamed Fares, Haytham O. Tawfik*, Claudiu T. Supuran*, Wagdy M. Eldehna* and Moataz A. Shaldam, ","doi":"10.1021/acs.jmedchem.5c0052610.1021/acs.jmedchem.5c00526","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.5c00526https://doi.org/10.1021/acs.jmedchem.5c00526","url":null,"abstract":"<p >This study investigates new anticonvulsant substances that target the epilepsy-associated carbonic anhydrase isoforms II and VII. The 1,2,3-triazole with a benzenesulfonamide motif is present in the produced molecules. Of these, <b>5b</b> and <b>5c</b> exhibited remarkable selectivity and inhibitory efficacy toward hCA VII and hCA II over hCA I. The <i>K</i><sub>I</sub> values of <b>5b</b> and <b>5c</b> were 6.3 and 10.1 nM, respectively, and 21.6 and 18.9 nM, respectively. In a pilocarpine-induced paradigm, <i>in vivo</i> assessments showed decreased seizure severity and susceptibility with delayed seizure onset and diminished intensity. The quick absorption and <i>in vivo</i> stability of <b>5b</b> were demonstrated by pharmacokinetic investigations. Evaluations of toxicity showed no neurotoxic effects and a high safety margin (LD<sub>50</sub> > 2000 mg/kg). Mechanistic research has shown effectiveness in maintaining neuronal integrity, reducing mTOR activation, and raising hippocampus KCC2 levels. Compound <b>5b</b>’s binding interactions with hCA II and hCA VII were clarified by docking and dynamics experiments.</p>","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"68 8","pages":"8873–8893 8873–8893"},"PeriodicalIF":6.8,"publicationDate":"2025-04-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143863239","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}
Protein ubiquitination is a reversible post-translational modification regulated by ubiquitin-conjugating and deubiquitinating enzymes (DUBs). Ubiquitin-specific protease 7 (USP7), a well-characterized DUB, plays multifaceted roles in various cellular processes, making it a promising therapeutic target. The plasticity of its catalytic domain and unique allosteric regulation by substrates or external or intramolecular factors facilitate the identification of highly selective USP7 inhibitors. These inhibitors can engage distinct ubiquitin-binding sites through covalent or non-covalent mechanisms. Despite its therapeutic promise, no USP7 inhibitors have entered clinical trials, underscoring the urgent need for novel therapeutics. Here we provide a crystallographic and functional landscape of USP7’s multilayer regulation and analyze the structure–activity relationship of inhibitors by chemotypes. Additionally, we explore USP7’s roles in diseases and discuss the challenges in USP7-targeted drug discovery and future directions for therapeutic development. This Perspective aims to provide a systematic overview of USP7, from its regulatory mechanisms to its therapeutic potential.
{"title":"Ubiquitin-Specific Protease 7 (USP7) as a Promising Therapeutic Target for Drug Discovery: From Mechanisms to Therapies","authors":"Yihui Song, Xiangli Ren, Jinbo Xiong, Wenwen Wang, Qianyan Zhao, Junbiao Chang, Bin Yu","doi":"10.1021/acs.jmedchem.5c00102","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.5c00102","url":null,"abstract":"Protein ubiquitination is a reversible post-translational modification regulated by ubiquitin-conjugating and deubiquitinating enzymes (DUBs). Ubiquitin-specific protease 7 (USP7), a well-characterized DUB, plays multifaceted roles in various cellular processes, making it a promising therapeutic target. The plasticity of its catalytic domain and unique allosteric regulation by substrates or external or intramolecular factors facilitate the identification of highly selective USP7 inhibitors. These inhibitors can engage distinct ubiquitin-binding sites through covalent or non-covalent mechanisms. Despite its therapeutic promise, no USP7 inhibitors have entered clinical trials, underscoring the urgent need for novel therapeutics. Here we provide a crystallographic and functional landscape of USP7’s multilayer regulation and analyze the structure–activity relationship of inhibitors by chemotypes. Additionally, we explore USP7’s roles in diseases and discuss the challenges in USP7-targeted drug discovery and future directions for therapeutic development. This Perspective aims to provide a systematic overview of USP7, from its regulatory mechanisms to its therapeutic potential.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"51 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2025-04-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143837621","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}
Pub Date : 2025-04-16DOI: 10.1021/acs.jmedchem.5c0067810.1021/acs.jmedchem.5c00678
Boqun Liu, Arthur Christopoulos, David M. Thal, Ben Capuano*, Celine Valant* and Peter J. Scammells*,
Since the serendipitous discovery of chlorpromazine in the 1950s, almost all current anti-schizophrenia drugs utilize the same mode of action by blocking the dopamine receptors in the brain. Unfortunately, these only treat part of the symptoms and are ineffective in almost 30% of patients. The recent FDA approval of Cobenfy, a coformulation of xanomeline, a M1/M4 muscarinic acetylcholine receptor (mAChR) agonist, and a peripherally restricted pan-mAChR blocker, has propelled the M4R as a validated and novel antipsychotic target. With >25 years of history in developing xanomeline, significant challenges remain in developing M4R activators, either at the ACh orthosteric binding site or allosterically via secondary less-conserved binding sites. Herein, we summarize recent successes and failures of M4R agonists and positive allosteric modulators, along with the progress in structure–activity relationship studies on both orthosteric and allosteric scaffolds to offer pathways for future therapeutics to this novel biological target for neuropsychiatric disorders.
{"title":"The Prosperity and Adversity of M4 Muscarinic Acetylcholine Receptor Activators in the Treatment of Neuropsychiatric Disorders","authors":"Boqun Liu, Arthur Christopoulos, David M. Thal, Ben Capuano*, Celine Valant* and Peter J. Scammells*, ","doi":"10.1021/acs.jmedchem.5c0067810.1021/acs.jmedchem.5c00678","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.5c00678https://doi.org/10.1021/acs.jmedchem.5c00678","url":null,"abstract":"<p >Since the serendipitous discovery of chlorpromazine in the 1950s, almost all current anti-schizophrenia drugs utilize the same mode of action by blocking the dopamine receptors in the brain. Unfortunately, these only treat part of the symptoms and are ineffective in almost 30% of patients. The recent FDA approval of Cobenfy, a coformulation of xanomeline, a M<sub>1</sub>/M<sub>4</sub> muscarinic acetylcholine receptor (mAChR) agonist, and a peripherally restricted pan-mAChR blocker, has propelled the M<sub>4</sub>R as a validated and novel antipsychotic target. With >25 years of history in developing xanomeline, significant challenges remain in developing M<sub>4</sub>R activators, either at the ACh orthosteric binding site or allosterically via secondary less-conserved binding sites. Herein, we summarize recent successes and failures of M<sub>4</sub>R agonists and positive allosteric modulators, along with the progress in structure–activity relationship studies on both orthosteric and allosteric scaffolds to offer pathways for future therapeutics to this novel biological target for neuropsychiatric disorders.</p>","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"68 8","pages":"7932–7954 7932–7954"},"PeriodicalIF":6.8,"publicationDate":"2025-04-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143863217","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}
Pub Date : 2025-04-16DOI: 10.1021/acs.jmedchem.5c00524
Yihui Song, Xiangli Ren, Xinyu Yang, Jinbo Xiong, Wenwen Wang, Kai Tang, Bin Yu
Src homology-2-containing protein tyrosine phosphatase 2 (SHP2) plays crucial roles in various biological processes and has become a promising target for cancer therapy. In this work, we presented the structure-guided design of new allosteric SHP2 inhibitors, leading to the identification of the pyrazolopyrimidinone derivatives TK-684 and TK-685. Both compounds were highly potent and selective allosteric SHP2 inhibitors (TK-684: SHP2WT IC50 = 2.1 nM; Ki = 0.89 nM; TK-685: SHP2WT IC50 = 1.5 nM; Ki = 0.87 nM), likely binding to the “tunnel” allosteric site of SHP2. By targeting SHP2-mediated AKT and ERK signaling pathways, TK-684 and TK-685 suppressed cell proliferation and induced apoptosis in esophageal cancer cells. Additionally, oral administration of TK-685 demonstrated good antitumor effects in the KYSE-150 xenograft mouse model, with a T/C value of 76.8%. Collectively, the pyrazolopyrimidinone derivatives represent promising lead compounds for the treatment of esophageal cancer, where SHP2 is dysregulated.
{"title":"Structure-Guided Design of Pyrazolopyrimidinones as Highly Potent and Selective Allosteric SHP2 Inhibitors","authors":"Yihui Song, Xiangli Ren, Xinyu Yang, Jinbo Xiong, Wenwen Wang, Kai Tang, Bin Yu","doi":"10.1021/acs.jmedchem.5c00524","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.5c00524","url":null,"abstract":"Src homology-2-containing protein tyrosine phosphatase 2 (SHP2) plays crucial roles in various biological processes and has become a promising target for cancer therapy. In this work, we presented the structure-guided design of new allosteric SHP2 inhibitors, leading to the identification of the pyrazolopyrimidinone derivatives <b>TK-684</b> and <b>TK-685</b>. Both compounds were highly potent and selective allosteric SHP2 inhibitors (<b>TK-684</b>: SHP2<sup>WT</sup> IC<sub>50</sub> = 2.1 nM; <i>K</i><sub><i>i</i></sub> = 0.89 nM; <b>TK-685</b>: SHP2<sup>WT</sup> IC<sub>50</sub> = 1.5 nM; <i>K</i><sub><i>i</i></sub> = 0.87 nM), likely binding to the “tunnel” allosteric site of SHP2. By targeting SHP2-mediated AKT and ERK signaling pathways, <b>TK-684</b> and <b>TK-685</b> suppressed cell proliferation and induced apoptosis in esophageal cancer cells. Additionally, oral administration of <b>TK-685</b> demonstrated good antitumor effects in the KYSE-150 xenograft mouse model, with a T/C value of 76.8%. Collectively, the pyrazolopyrimidinone derivatives represent promising lead compounds for the treatment of esophageal cancer, where SHP2 is dysregulated.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"74 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2025-04-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143837494","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}
Pub Date : 2025-04-16DOI: 10.1021/acs.jmedchem.4c02580
Jianping Lin, Rongjun He, Zihan Qu, Jiajun Dong, Aaron D. Krabill, Li Wu, Yunpeng Bai, Lindsey R. Conroy, Ronald C. Bruntz, Yiming Miao, Brenson A. Jassim, Benjamin Babalola, Frederick Georges Bernard Nguele Meke, Ramon Sun, Matthew S. Gentry, Zhong-Yin Zhang
Lafora disease is a rare and fatal progressive myoclonus epilepsy characterized by the accumulation of insoluble glycogen deposits in the brain and peripheral tissues. Mutations in the gene encoding the glycogen phosphatase laforin result in Lafora disease. Currently, there are no laforin-specific chemical probes, limiting our understanding of the roles of laforin in glycogen metabolism and other cellular processes. Here, we identified sulfophenyl acetic amide (SPAA), as a novel nonhydrolyzable phosphotyrosine mimetic for laforin inhibition. Using fragment-based and scaffold-hopping strategies, we discovered several highly potent and selective active site-directed laforin inhibitors. Among them, compound 9c displayed a Ki value of 1.9 ± 0.2 nM and more than 8300-fold preference for laforin. Moreover, these inhibitors efficiently block laforin-mediated glucan dephosphorylation inside the cell and possess favorable pharmacokinetic properties in mice. These chemical probes will enable further investigation of the roles of laforin in normal physiological processes and in diseases.
{"title":"Discovery and Evaluation of Active Site-Directed, Potent, and Selective Sulfophenyl Acetic Amide-Based Inhibitors for the Laforin Phosphatase","authors":"Jianping Lin, Rongjun He, Zihan Qu, Jiajun Dong, Aaron D. Krabill, Li Wu, Yunpeng Bai, Lindsey R. Conroy, Ronald C. Bruntz, Yiming Miao, Brenson A. Jassim, Benjamin Babalola, Frederick Georges Bernard Nguele Meke, Ramon Sun, Matthew S. Gentry, Zhong-Yin Zhang","doi":"10.1021/acs.jmedchem.4c02580","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.4c02580","url":null,"abstract":"Lafora disease is a rare and fatal progressive myoclonus epilepsy characterized by the accumulation of insoluble glycogen deposits in the brain and peripheral tissues. Mutations in the gene encoding the glycogen phosphatase laforin result in Lafora disease. Currently, there are no laforin-specific chemical probes, limiting our understanding of the roles of laforin in glycogen metabolism and other cellular processes. Here, we identified sulfophenyl acetic amide (SPAA), as a novel nonhydrolyzable phosphotyrosine mimetic for laforin inhibition. Using fragment-based and scaffold-hopping strategies, we discovered several highly potent and selective active site-directed laforin inhibitors. Among them, compound <b>9c</b> displayed a <i>K</i><sub><i>i</i></sub> value of 1.9 ± 0.2 nM and more than 8300-fold preference for laforin. Moreover, these inhibitors efficiently block laforin-mediated glucan dephosphorylation inside the cell and possess favorable pharmacokinetic properties in mice. These chemical probes will enable further investigation of the roles of laforin in normal physiological processes and in diseases.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"64 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2025-04-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143841274","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}
Pub Date : 2025-04-16DOI: 10.1021/acs.jmedchem.5c00390
Olaf Kinzel, Steven D. Goldberg, Maxwell D. Cummings, Christian Gege, Christoph Steeneck, Xiaohua Xue, Michael Albers, Thomas Schlüter, Gerald Kleymann, Brian Scott, Kia Sepassi, Freddy Schoetens, Hariharan Venkatesan, Virginia M. Tanis, Kevin Coe, Zachary S. Sales, John Spurlino, Cynthia Milligan, Anne M. Fourie, James P. Edwards, Thomas Hoffmann
The retinoic acid receptor-related orphan receptor gamma t (RORγt) is a nuclear transcription factor expressed in both innate and adaptive immune cells, driving Th17 cell differentiation and IL-17 production. The IL-23/IL-17 pathway is implicated in autoimmune and inflammatory diseases, and biologics that target IL-23/IL-17 signaling are efficacious in the treatment of psoriasis and psoriatic arthritis. RORγt, at the core of this pathway, represents an attractive opportunity for small-molecule intervention; however, combining high potency, nuclear receptor selectivity, and good physicochemical properties remains a challenge for RORγt inverse agonists. Recently, thiazole amides have been identified as potent RORγt inverse agonists; however, they often suffer from CYP450 autoinduction in the rat, precluding further development. Herein, we describe the discovery and development of potent and selective thiazole bisamide RORγt inverse agonists that avoid autoinduction in the rat. This effort culminated in the discovery of JNJ-61803534, which advanced into phase 1 clinical trials.
{"title":"Identification of JNJ-61803534, a RORγt Inverse Agonist for the Treatment of Psoriasis","authors":"Olaf Kinzel, Steven D. Goldberg, Maxwell D. Cummings, Christian Gege, Christoph Steeneck, Xiaohua Xue, Michael Albers, Thomas Schlüter, Gerald Kleymann, Brian Scott, Kia Sepassi, Freddy Schoetens, Hariharan Venkatesan, Virginia M. Tanis, Kevin Coe, Zachary S. Sales, John Spurlino, Cynthia Milligan, Anne M. Fourie, James P. Edwards, Thomas Hoffmann","doi":"10.1021/acs.jmedchem.5c00390","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.5c00390","url":null,"abstract":"The retinoic acid receptor-related orphan receptor gamma t (RORγt) is a nuclear transcription factor expressed in both innate and adaptive immune cells, driving Th17 cell differentiation and IL-17 production. The IL-23/IL-17 pathway is implicated in autoimmune and inflammatory diseases, and biologics that target IL-23/IL-17 signaling are efficacious in the treatment of psoriasis and psoriatic arthritis. RORγt, at the core of this pathway, represents an attractive opportunity for small-molecule intervention; however, combining high potency, nuclear receptor selectivity, and good physicochemical properties remains a challenge for RORγt inverse agonists. Recently, thiazole amides have been identified as potent RORγt inverse agonists; however, they often suffer from CYP450 autoinduction in the rat, precluding further development. Herein, we describe the discovery and development of potent and selective thiazole bisamide RORγt inverse agonists that avoid autoinduction in the rat. This effort culminated in the discovery of JNJ-61803534, which advanced into phase 1 clinical trials.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"1 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2025-04-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143837620","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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