Pub Date : 2025-03-05DOI: 10.1021/acs.jmedchem.4c02658
Tao Bi, Pan Liang, Qixin Zhao, Jiao Wu, Yanan Zhou, Yunke Xu, Xuehui Fan, Guoqiang Yang, Qin Sun, Wei Ren, Yingcheng Yang, Zengjin Liu
Liver fibrosis is an inadequate response to tissue stress, with reactive oxygen species (ROS) overproduction in activated hepatic stellate cells (aHSCs). Bromodomain-containing protein 4 (BRD4) was found to be upregulated in aHSCs and has been identified as an effective target for the treatment of liver fibrosis. However, inhibition of BRD4 with traditional kinase inhibitors achieved only limited success because of its low therapeutic efficiency. Furthermore, the exact mechanism by which BRD4 regulates liver fibrosis remains unclear and needs to be elucidated. In this work, we proposed an efficiency strategy, i.e., targeted degradation of BRD4 by ROS-activatable NanoPROTACs, for the treatment of liver fibrosis, both in vitro and in vivo. More importantly, we clarified the mechanism by which BRD4 regulates liver fibrosis. Thus, this strategy may represent an alternative to previously reported strategies and may be extensively applied to the design of ROS-activatable proteolysis-targeting chimeras for the treatment of other organ fibrosis.
{"title":"Targeted Degradation of Bromodomain-Containing Protein 4 Enabled by Reactive Oxygen Species–Activatable NanoPROTACs as an Efficient Strategy to Reverse Liver Fibrosis in Chronic Liver Injury","authors":"Tao Bi, Pan Liang, Qixin Zhao, Jiao Wu, Yanan Zhou, Yunke Xu, Xuehui Fan, Guoqiang Yang, Qin Sun, Wei Ren, Yingcheng Yang, Zengjin Liu","doi":"10.1021/acs.jmedchem.4c02658","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.4c02658","url":null,"abstract":"Liver fibrosis is an inadequate response to tissue stress, with reactive oxygen species (ROS) overproduction in activated hepatic stellate cells (aHSCs). Bromodomain-containing protein 4 (BRD4) was found to be upregulated in aHSCs and has been identified as an effective target for the treatment of liver fibrosis. However, inhibition of BRD4 with traditional kinase inhibitors achieved only limited success because of its low therapeutic efficiency. Furthermore, the exact mechanism by which BRD4 regulates liver fibrosis remains unclear and needs to be elucidated. In this work, we proposed an efficiency strategy, i.e., targeted degradation of BRD4 by ROS-activatable NanoPROTACs, for the treatment of liver fibrosis, both <i>in vitro</i> and <i>in vivo</i>. More importantly, we clarified the mechanism by which BRD4 regulates liver fibrosis. Thus, this strategy may represent an alternative to previously reported strategies and may be extensively applied to the design of ROS-activatable proteolysis-targeting chimeras for the treatment of other organ fibrosis.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"11 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2025-03-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143561253","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 : 2025-03-05DOI: 10.1021/acs.jmedchem.4c02906
Sean M. Carney, Sandrine Grosse, Yanting Yin, Minh T. Tran, Jay H. Kalin, Edgar Jacoby, Amy Fung, Nicholas Simmons, Xiaoming Xie, Anusarka Bhaumik, Rodrigo J. Carbajo, Madison Piassek, Robyn Miller, Lili Hu, Cynthia Lemmens, Ferdinand H. Lutter, Serge Pieters, Geert Rombouts, Irene Vetrano, Daniel Oehlrich, Sonia Tomaso, Kate Lozada, Miguel Osorio Garcia, Brandon Anson, Suzanne De Bruyn, Constance Smith-Monroy, Jean-Marc Neefs, Nádia Conceição-Neto, Bart Kesteleyn, Roberto Fino, Bart Stoops, Herman van Vlijmen, Aaron N. Patrick, Xiaodi Yu, Victoria Wong, Daniel J. Krosky, Pravien Abeywickrema, Rodrigo F. Ortiz-Meoz, Stephen W. Mason, Zhinan Jin, Sujata Sharma, Tim H. M. Jonckers
Respiratory syncytial virus (RSV) remains a public health burden due to unmet therapeutic needs. We recently reported the discovery of a non-nucleoside inhibitor of the RSV polymerase and characterized its binding to a novel pocket within the capping domain of the polymerase. Here, we describe our strategy to diversify the chemical matter targeting this site by screening our DNA-encoded chemical libraries, leading to the discovery of a novel and potent series of molecules that inhibits RSV polymerase’s biochemical activity, as well as its viral replication in cells. Structural analysis via cryo-EM revealed novel contacts made within the capping domain binding pocket. By leveraging these structural insights for preliminary SAR exploration, we generated analogues for which potency and metabolic stability were improved more than 60- and 40-fold, respectively, over the initial hit. This work provides a path forward for further advanced SAR exploration and development of therapeutics against RSV.
{"title":"DNA-Encoded Library Screen Identifies Novel Series of Respiratory Syncytial Virus Polymerase Inhibitors","authors":"Sean M. Carney, Sandrine Grosse, Yanting Yin, Minh T. Tran, Jay H. Kalin, Edgar Jacoby, Amy Fung, Nicholas Simmons, Xiaoming Xie, Anusarka Bhaumik, Rodrigo J. Carbajo, Madison Piassek, Robyn Miller, Lili Hu, Cynthia Lemmens, Ferdinand H. Lutter, Serge Pieters, Geert Rombouts, Irene Vetrano, Daniel Oehlrich, Sonia Tomaso, Kate Lozada, Miguel Osorio Garcia, Brandon Anson, Suzanne De Bruyn, Constance Smith-Monroy, Jean-Marc Neefs, Nádia Conceição-Neto, Bart Kesteleyn, Roberto Fino, Bart Stoops, Herman van Vlijmen, Aaron N. Patrick, Xiaodi Yu, Victoria Wong, Daniel J. Krosky, Pravien Abeywickrema, Rodrigo F. Ortiz-Meoz, Stephen W. Mason, Zhinan Jin, Sujata Sharma, Tim H. M. Jonckers","doi":"10.1021/acs.jmedchem.4c02906","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.4c02906","url":null,"abstract":"Respiratory syncytial virus (RSV) remains a public health burden due to unmet therapeutic needs. We recently reported the discovery of a non-nucleoside inhibitor of the RSV polymerase and characterized its binding to a novel pocket within the capping domain of the polymerase. Here, we describe our strategy to diversify the chemical matter targeting this site by screening our DNA-encoded chemical libraries, leading to the discovery of a novel and potent series of molecules that inhibits RSV polymerase’s biochemical activity, as well as its viral replication in cells. Structural analysis via cryo-EM revealed novel contacts made within the capping domain binding pocket. By leveraging these structural insights for preliminary SAR exploration, we generated analogues for which potency and metabolic stability were improved more than 60- and 40-fold, respectively, over the initial hit. This work provides a path forward for further advanced SAR exploration and development of therapeutics against RSV.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"211 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2025-03-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143545884","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 : 2025-03-05DOI: 10.1021/acs.jmedchem.5c00539
Changhong Wei, Yun Liu, Zhiming Yan, Jing Han, Neng Jiang
Dual modulation of FXR and HSD17B13 presents a promising strategy for treating metabolic dysfunction-associated fatty liver disease (MAFLD) and metabolic dysfunction-associated steatohepatitis (MASH). Compound 6, a groundbreaking dual modulator of FXR and HSD17B13, validates the concept of significantly enhancing liver function, reducing inflammation and fibrosis across various MAFLD models.
{"title":"Dual Modulator of FXR and HSD17B13: Revitalizing FXR Therapies in MASH","authors":"Changhong Wei, Yun Liu, Zhiming Yan, Jing Han, Neng Jiang","doi":"10.1021/acs.jmedchem.5c00539","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.5c00539","url":null,"abstract":"Dual modulation of FXR and HSD17B13 presents a promising strategy for treating metabolic dysfunction-associated fatty liver disease (MAFLD) and metabolic dysfunction-associated steatohepatitis (MASH). Compound <b>6</b>, a groundbreaking dual modulator of FXR and HSD17B13, validates the concept of significantly enhancing liver function, reducing inflammation and fibrosis across various MAFLD models.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"53 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2025-03-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143561254","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 : 2025-03-04DOI: 10.1021/acs.jmedchem.4c02759
Dong-Ming Shen, Kate F. Byth, Damien Bertheloot, Simona Braams, Sarah Bradley, Dennis Dean, Carien Dekker, Ayman F. El-Kattan, Luigi Franchi, Gary D. Glick, Shomir Ghosh, Alexandra Hinniger, Jason D. Katz, Ana Kitanovic, Xiaokang Lu, Edward J. Olhava, Anthony W. Opipari, Brian Sanchez, H. Martin Seidel, James Stunden, Andrea Stutz, Alissa Telling, Shankar Venkatraman, David G. Winkler, William R. Roush
The discovery of DFV890 ((R)-1), a potent and selective NLRP3 antagonist, is described. Replacement of the sulfonyl urea core from the first-generation NLRP3 antagonist CRID3 with a sulfonimidamide core afforded a novel and potent series of NLRP3 antagonists. The (R)-enantiomers of the sulfonimidamide series were found to be consistently more potent than structurally related sulfonyl ureas. Replacement of the furan unit of CRID3 with a 5-substituted thiazole unit led to DFV890 ((R)-1), which potently inhibited IL-1β production in THP-1 cells and in primary human cells, blocked multiple downstream effectors of NLRP3 activation, and substantially improved PK properties and significantly lowered the predicted human dose compared to that for CRID3. DFV890 ((R)-1) was also effective in an air pouch model of gout.
{"title":"Discovery of DFV890, a Potent Sulfonimidamide-Containing NLRP3 Inflammasome Inhibitor","authors":"Dong-Ming Shen, Kate F. Byth, Damien Bertheloot, Simona Braams, Sarah Bradley, Dennis Dean, Carien Dekker, Ayman F. El-Kattan, Luigi Franchi, Gary D. Glick, Shomir Ghosh, Alexandra Hinniger, Jason D. Katz, Ana Kitanovic, Xiaokang Lu, Edward J. Olhava, Anthony W. Opipari, Brian Sanchez, H. Martin Seidel, James Stunden, Andrea Stutz, Alissa Telling, Shankar Venkatraman, David G. Winkler, William R. Roush","doi":"10.1021/acs.jmedchem.4c02759","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.4c02759","url":null,"abstract":"The discovery of DFV890 ((<i>R</i>)-<b>1</b>), a potent and selective NLRP3 antagonist, is described. Replacement of the sulfonyl urea core from the first-generation NLRP3 antagonist CRID3 with a sulfonimidamide core afforded a novel and potent series of NLRP3 antagonists. The <i>(R)-</i>enantiomers of the sulfonimidamide series were found to be consistently more potent than structurally related sulfonyl ureas. Replacement of the furan unit of CRID3 with a 5-substituted thiazole unit led to DFV890 ((<i>R</i>)-<b>1</b>), which potently inhibited IL-1β production in THP-1 cells and in primary human cells, blocked multiple downstream effectors of NLRP3 activation, and substantially improved PK properties and significantly lowered the predicted human dose compared to that for CRID3. DFV890 ((<i>R</i>)-<b>1</b>) was also effective in an air pouch model of gout.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"30 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2025-03-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143545873","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 : 2025-03-04DOI: 10.1021/acs.jmedchem.4c03146
Kaiyue Liu, Yunyun Ji, Yiming Xie, Chengyan Wang, Jie Zhou, Ziyi Wei, Xiaoyu Wang, Xiaotong Zheng, Yao Cen, Fan Zhang, Bailing Xu
TREK-1 regulates neuronal excitability and neuronal cell apoptosis, and inhibition of TREK-1 is a potential strategy to prevent cell death and achieve neuroprotection in an ischemic stroke. In this work, a series of novel isobenzofuran-1(3H)-one derivatives were designed and synthesized as TREK-1 inhibitors, and extensive structure–activity relationships led to the discovery of potent and selective TREK-1 inhibitors having IC50 values of a low micromolar level. Among them, Cpd8l potently and selectively inhibited TREK-1 (IC50 = 0.81 μM, selectivity >30 fold over other K+, Na+, and TRP channels). Cpd8l remarkably reduced the neuron death in the OGD/R-induced cortical neuronal injury model, while adenovirus silencing TREK-1 reduced its neuroprotective effect. Furthermore, Cpd8l could effectively ameliorate brain injury in MCAO/R model mice. Collectively, this work demonstrates that Cpd8l may serve as a novel lead compound to develop a highly potent and selective TREK-1 inhibitor for ischemic stroke treatment.
{"title":"Discovery of Isobenzofuran-1(3H)-one Derivatives as Selective TREK-1 Inhibitors with In Vitro and In Vivo Neuroprotective Effects","authors":"Kaiyue Liu, Yunyun Ji, Yiming Xie, Chengyan Wang, Jie Zhou, Ziyi Wei, Xiaoyu Wang, Xiaotong Zheng, Yao Cen, Fan Zhang, Bailing Xu","doi":"10.1021/acs.jmedchem.4c03146","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.4c03146","url":null,"abstract":"TREK-1 regulates neuronal excitability and neuronal cell apoptosis, and inhibition of TREK-1 is a potential strategy to prevent cell death and achieve neuroprotection in an ischemic stroke. In this work, a series of novel isobenzofuran-1(3<i>H</i>)-one derivatives were designed and synthesized as TREK-1 inhibitors, and extensive structure–activity relationships led to the discovery of potent and selective TREK-1 inhibitors having IC<sub>50</sub> values of a low micromolar level. Among them, <b>Cpd8l</b> potently and selectively inhibited TREK-1 (IC<sub>50</sub> = 0.81 μM, selectivity >30 fold over other K<sup>+</sup>, Na<sup>+</sup>, and TRP channels). <b>Cpd8l</b> remarkably reduced the neuron death in the OGD/R-induced cortical neuronal injury model, while adenovirus silencing TREK-1 reduced its neuroprotective effect. Furthermore, <b>Cpd8l</b> could effectively ameliorate brain injury in MCAO/R model mice. Collectively, this work demonstrates that <b>Cpd8l</b> may serve as a novel lead compound to develop a highly potent and selective TREK-1 inhibitor for ischemic stroke treatment.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"67 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2025-03-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143545887","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 : 2025-03-04DOI: 10.1021/acs.jmedchem.5c00258
Zhaomin Xia, Qiumei Zhu, Yi Shan, Jiayu Lu, Meidi An, Xiaoxue Mo, Siqi Wang, Wen Yang, Hua Qian, Huaizhen He, Cheng Wang
Mas-related G protein-coupled receptor X2 (MrgX2) plays a key role in pseudoallergy reactions; thus, it is of great significance to screen compounds with antipseudoallergy activity via MrgX2. Cell membrane chromatography (CMC) demonstrates great potential in drug screening, but it requires further optimization to improve its specificity and stability. In this study, a new CMC system incorporating His-tag-oriented immobilized proteins was constructed to screen MrgX2 antagonists. Single His-tag-fused MrgX2 was extracted intactly and covalently bond to divinyl sulfone-modified amino silica gel to obtain bioaffinity composites. The characterized composites were utilized to establish a MrgX2-His-tag@VS/CMC system to screen MrgX2 antagonists. Compound Z-3578 was screened from a G protein-coupled receptor compound library of 3010 compounds and revealed its efficient antipseudoallergy activity in vitro and in vivo via MrgX2. In conclusion, the new oriented-immobilized CMC system will provide an efficient analytical tool for screening active precursors.
{"title":"MrgX2-Targeting Ligand Screen for Antipseudoallergic Agents by Immobilized His-Tag-Fused Protein Technology","authors":"Zhaomin Xia, Qiumei Zhu, Yi Shan, Jiayu Lu, Meidi An, Xiaoxue Mo, Siqi Wang, Wen Yang, Hua Qian, Huaizhen He, Cheng Wang","doi":"10.1021/acs.jmedchem.5c00258","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.5c00258","url":null,"abstract":"Mas-related G protein-coupled receptor X2 (MrgX2) plays a key role in pseudoallergy reactions; thus, it is of great significance to screen compounds with antipseudoallergy activity via MrgX2. Cell membrane chromatography (CMC) demonstrates great potential in drug screening, but it requires further optimization to improve its specificity and stability. In this study, a new CMC system incorporating His-tag-oriented immobilized proteins was constructed to screen MrgX2 antagonists. Single His-tag-fused MrgX2 was extracted intactly and covalently bond to divinyl sulfone-modified amino silica gel to obtain bioaffinity composites. The characterized composites were utilized to establish a MrgX2-His-tag@VS/CMC system to screen MrgX2 antagonists. Compound Z-3578 was screened from a G protein-coupled receptor compound library of 3010 compounds and revealed its efficient antipseudoallergy activity in vitro and in vivo via MrgX2. In conclusion, the new oriented-immobilized CMC system will provide an efficient analytical tool for screening active precursors.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"35 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2025-03-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143545876","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 : 2025-03-04DOI: 10.1021/acs.jmedchem.4c03067
Kevin M. Cottrell, Kimberly J. Briggs, Alice Tsai, Matthew R. Tonini, Douglas A. Whittington, Shanzhong Gong, Colin Liang, Patrick McCarren, Minjie Zhang, Wenhai Zhang, Alan Huang, John P. Maxwell
The gene encoding for MTAP is one of the most commonly deleted genes in cancer, occurring in approximately 10–15% of all human cancer. We have previously described the discovery of TNG908, a brain-penetrant clinical-stage compound that selectively targets MTAP-deleted cancer cells by binding to and inhibiting PRMT5 cooperatively with MTA, which is present in elevated concentrations in MTAP-deleted cells. Herein we describe the discovery of TNG462, a more potent and selective MTA-cooperative PRMT5 inhibitor with improved DMPK properties that is selective for MTAP-deleted cancers and is currently in Phase I/II clinical trials.
{"title":"Discovery of TNG462: A Highly Potent and Selective MTA-Cooperative PRMT5 Inhibitor to Target Cancers with MTAP Deletion","authors":"Kevin M. Cottrell, Kimberly J. Briggs, Alice Tsai, Matthew R. Tonini, Douglas A. Whittington, Shanzhong Gong, Colin Liang, Patrick McCarren, Minjie Zhang, Wenhai Zhang, Alan Huang, John P. Maxwell","doi":"10.1021/acs.jmedchem.4c03067","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.4c03067","url":null,"abstract":"The gene encoding for MTAP is one of the most commonly deleted genes in cancer, occurring in approximately 10–15% of all human cancer. We have previously described the discovery of TNG908, a brain-penetrant clinical-stage compound that selectively targets <i>MTAP</i>-deleted cancer cells by binding to and inhibiting PRMT5 cooperatively with MTA, which is present in elevated concentrations in <i>MTAP</i>-deleted cells. Herein we describe the discovery of TNG462, a more potent and selective MTA-cooperative PRMT5 inhibitor with improved DMPK properties that is selective for <i>MTAP</i>-deleted cancers and is currently in Phase I/II clinical trials.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"9 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2025-03-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143538749","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 : 2025-03-04DOI: 10.1021/acs.jmedchem.4c03158
Purav P. Vagadia, Javier Izquierdo-Ferrer, Candice Mazewski, Gavin Blyth, Elspeth M. Beauchamp, Matthew R. Clutter, Charlotte L. Stern, Rama K. Mishra, Dominik Nahotko, Sara Small, Frank Eckerdt, Leonidas C. Platanias, Gary E. Schiltz
MNK activity is regulated by the p38 and Erk MAPK pathways. Phosphorylation of MNK leads to its activation and binding to the eIF4G/eIF4E complex. MNK then phosphorylates eIF4E at Ser209, whose activation is associated with oncogene translation, leading to tumorigenesis. Given this important role for eIF4E in tumorigenesis, MNK inhibition with novel small molecule inhibitors could be a promising strategy to combat AML, which continues to be an area of unmet medical need. Here, we report the medicinal optimization of a series of novel inhibitors and their evaluation of their effects on eIF4E and leukemia cell viability. We discovered a class of ether-containing compounds with a high MNK1/2 selectivity. These MNK inhibitors show good potency in reducing cell viability and colony formation and have desirable pharmacokinetic properties. X-ray cocrystallization was accomplished to confirm the binding mode of our inhibitors and aid in future optimization.
{"title":"Discovery of Potent and Selective MNK Kinase Inhibitors for the Treatment of Leukemia","authors":"Purav P. Vagadia, Javier Izquierdo-Ferrer, Candice Mazewski, Gavin Blyth, Elspeth M. Beauchamp, Matthew R. Clutter, Charlotte L. Stern, Rama K. Mishra, Dominik Nahotko, Sara Small, Frank Eckerdt, Leonidas C. Platanias, Gary E. Schiltz","doi":"10.1021/acs.jmedchem.4c03158","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.4c03158","url":null,"abstract":"MNK activity is regulated by the p38 and Erk MAPK pathways. Phosphorylation of MNK leads to its activation and binding to the eIF4G/eIF4E complex. MNK then phosphorylates eIF4E at Ser209, whose activation is associated with oncogene translation, leading to tumorigenesis. Given this important role for eIF4E in tumorigenesis, MNK inhibition with novel small molecule inhibitors could be a promising strategy to combat AML, which continues to be an area of unmet medical need. Here, we report the medicinal optimization of a series of novel inhibitors and their evaluation of their effects on eIF4E and leukemia cell viability. We discovered a class of ether-containing compounds with a high MNK1/2 selectivity. These MNK inhibitors show good potency in reducing cell viability and colony formation and have desirable pharmacokinetic properties. X-ray cocrystallization was accomplished to confirm the binding mode of our inhibitors and aid in future optimization.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"211 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2025-03-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143538753","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}
Src homology-2-containing protein tyrosine phosphatase (PTP) 2 (SHP2) is a pivotal PTP that modulates key cellular processes including proliferation, differentiation, and migration. Its overexpression is implicated in the pathogenesis of various malignancies, highlighting the need for effective SHP2 inhibitors. Herein, we report the design and synthesis of a novel series of thiazolo[5,4-b]pyridine and imidazo[1,2-c]pyrimidine derivatives as SHP2 allosteric inhibitors identified through active fragment splicing. The synthesized compounds exhibited potent SHP2 inhibition, with IC50 values ranging from 9.0 to 34.5 nM. Notably, compound B8 demonstrated superior potency, with an IC50 of 0.04 μM for p-ERK modulation. Compound B8 also displayed favorable drug-like properties and significant antitumor activity in a KYSE520 xenograft mouse model, underscoring its potential as a lead candidate for further development. Our findings provide a foundation for the advancement of SHP2-targeted therapeutics.
{"title":"Development of Potent SHP2 Allosteric Inhibitors: Design, Synthesis, and Evaluation with Antitumor Effects","authors":"Cheng Shi, Yanping Zhao, Han Huang, Jiaxu Zhou, Dehua Lu, Yanming Chen, Weiping Lyu, Zhenming Liu, Hongjun Wang, Liangren Zhang","doi":"10.1021/acs.jmedchem.4c02100","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.4c02100","url":null,"abstract":"Src homology-2-containing protein tyrosine phosphatase (PTP) 2 (SHP2) is a pivotal PTP that modulates key cellular processes including proliferation, differentiation, and migration. Its overexpression is implicated in the pathogenesis of various malignancies, highlighting the need for effective SHP2 inhibitors. Herein, we report the design and synthesis of a novel series of thiazolo[5,4-<i>b</i>]pyridine and imidazo[1,2-<i>c</i>]pyrimidine derivatives as SHP2 allosteric inhibitors identified through active fragment splicing. The synthesized compounds exhibited potent SHP2 inhibition, with IC<sub>50</sub> values ranging from 9.0 to 34.5 nM. Notably, compound <b>B8</b> demonstrated superior potency, with an IC<sub>50</sub> of 0.04 μM for p-ERK modulation. Compound <b>B8</b> also displayed favorable drug-like properties and significant antitumor activity in a KYSE520 xenograft mouse model, underscoring its potential as a lead candidate for further development. Our findings provide a foundation for the advancement of SHP2-targeted therapeutics.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"46 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2025-03-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143538748","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 : 2025-03-04DOI: 10.1021/acs.jmedchem.4c03120
Chad R. Schultz, Bilal Aleiwi, X. Edward Zhou, Kelly Suino-Powell, Karsten Melcher, Nuno M. S. Almeida, Angela K. Wilson, Edmund L. Ellsworth, André S. Bachmann
We here describe the design, synthesis, and biological activity of novel ornithine decarboxylase (ODC) inhibitors that show significantly higher potency in vitro than α-difluoromethylornithine (DFMO), a U.S. Food and Drug Administration (FDA) approved drug. We report two X-ray structures of ODC complexed with new ODC inhibitors, computational docking, molecular dynamics, and binding free energy calculations to validate the experimental models. The X-ray structures reveal that covalent adducts with pyridoxal phosphate (PLP) are formed in the active site of the human ODC enzyme, as verified by their preparation and enzymatic testing. Finally, we verified that the cellular activity of endogenous ODC was inhibited, and polyamine levels were reduced. Given that ODC is a clinically validated target, combined with the fact that DFMO is currently the only ODC inhibitor in clinical use for several indications, the further development of more potent ODC inhibitors with superior activity and physical properties is warranted.
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