Pub Date : 2025-01-22DOI: 10.1021/acs.jmedchem.4c02689
Xuemei Deng, Yuying Wang, Xiongqi Yang, Quanwei Yu, Ridong Huang, Hai Chen, Weimin Li, Yang He
To overcome the compensatory effect between Topo I and II, one of the reasons accounting for the resistance of SCLC patients, we are pioneering the use of 3-arylisoquinolines to develop dual inhibitors of Topo I/II for the management of SCLC. A total of 46 new compounds were synthesized. Compounds 3g (IC50 = 1.30 μM for NCI-H446 cells and 1.42 μM for NCI-H1048 cells) and 3x (IC50 = 1.32 μM for NCI-H446 cells and 2.45 μM for NCI-H1048 cells) were selected for detailed pharmacological investigation, due to their outstanding cytotoxicity and dual Topo I and II inhibitory activity. 3g and 3x effectively prevent SCLC cell proliferation, invasion, and migration in vitro, byinducing mitochondrial apoptosis and inhibiting the PI3K/Akt/mTOR pathway. Their in vivo tumor inhibition rate is comparable to etoposide with lower toxicity. These results indicated their potential therapeutic values as dual Topo I and II inhibitors for treating SCLC.
{"title":"Synthesis, Structural Modification, and Antismall Cell Lung Cancer Activity of 3-Arylisoquinolines with Dual Inhibitory Activity on Topoisomerase I and II","authors":"Xuemei Deng, Yuying Wang, Xiongqi Yang, Quanwei Yu, Ridong Huang, Hai Chen, Weimin Li, Yang He","doi":"10.1021/acs.jmedchem.4c02689","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.4c02689","url":null,"abstract":"To overcome the compensatory effect between Topo I and II, one of the reasons accounting for the resistance of SCLC patients, we are pioneering the use of 3-arylisoquinolines to develop dual inhibitors of Topo I/II for the management of SCLC. A total of 46 new compounds were synthesized. Compounds <b>3g</b> (IC<sub>50</sub> = 1.30 μM for NCI-H446 cells and 1.42 μM for NCI-H1048 cells) and <b>3x</b> (IC<sub>50</sub> = 1.32 μM for NCI-H446 cells and 2.45 μM for NCI-H1048 cells) were selected for detailed pharmacological investigation, due to their outstanding cytotoxicity and dual Topo I and II inhibitory activity. <b>3g</b> and <b>3x</b> effectively prevent SCLC cell proliferation, invasion, and migration <i>in vitro</i>, byinducing mitochondrial apoptosis and inhibiting the PI3K/Akt/mTOR pathway. Their <i>in vivo</i> tumor inhibition rate is comparable to etoposide with lower toxicity. These results indicated their potential therapeutic values as dual Topo I and II inhibitors for treating SCLC.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"4 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2025-01-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143020380","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 : 2025-01-22DOI: 10.1021/acs.jmedchem.4c02531
Sophia M. Min, Frances M. Bashore, Jeffery L. Smith, Tammy M. Havener, Stefanie Howell, Haoxi Li, Rafael M. Couñago, Konstantin I. Popov, Alison D. Axtman
We optimized our highly potent and cell-active chemical probe for phosphatidylinositol-3-phosphate 5-kinase (PIKfyve), SGC-PIKFYVE-1, resulting in compounds with improved potency and demonstrated in vivo stability. Use of an in-cell, kinome-wide selectivity panel allowed for confirmation of excellent in-cell selectivity of our lead compound, 40, and another promising analogue, 46. Evaluation of the pharmacokinetic (PK) profiles of these two compounds revealed that both are well tolerated systemically and orally bioavailable. Coupled with its subnanomolar cellular potency and impressive selectivity in cells, the long half-life of 40 makes it an ideal candidate for the evaluation of the consequences of PIKfyve inhibition in vivo. PIKfyve inhibition has been investigated clinically for indications including rheumatoid arthritis, Crohn’s disease, COVID-19, and ALS using a single compound (apilimod), supporting the development of orthogonal PIKfyve inhibitors with in vivo stability.
{"title":"Development of a Second-Generation, In Vivo Chemical Probe for PIKfyve","authors":"Sophia M. Min, Frances M. Bashore, Jeffery L. Smith, Tammy M. Havener, Stefanie Howell, Haoxi Li, Rafael M. Couñago, Konstantin I. Popov, Alison D. Axtman","doi":"10.1021/acs.jmedchem.4c02531","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.4c02531","url":null,"abstract":"We optimized our highly potent and cell-active chemical probe for phosphatidylinositol-3-phosphate 5-kinase (PIKfyve), SGC-PIKFYVE-1, resulting in compounds with improved potency and demonstrated <i>in vivo</i> stability. Use of an in-cell, kinome-wide selectivity panel allowed for confirmation of excellent in-cell selectivity of our lead compound, <b>40</b>, and another promising analogue, <b>46</b>. Evaluation of the pharmacokinetic (PK) profiles of these two compounds revealed that both are well tolerated systemically and orally bioavailable. Coupled with its subnanomolar cellular potency and impressive selectivity in cells, the long half-life of <b>40</b> makes it an ideal candidate for the evaluation of the consequences of PIKfyve inhibition <i>in vivo</i>. PIKfyve inhibition has been investigated clinically for indications including rheumatoid arthritis, Crohn’s disease, COVID-19, and ALS using a single compound (apilimod), supporting the development of orthogonal PIKfyve inhibitors with <i>in vivo</i> stability.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"10 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2025-01-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142992051","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 : 2025-01-22DOI: 10.1021/acs.jmedchem.4c02563
Sanyong Zhu, Zhenfeng Song, April Sweet Tapayan, Kartikey Singh, Kuang-Wei Wang, Hsiao-Tien Chien Hagar, Jicheng Zhang, Hyunbae Kim, Patty Thepsuwan, Min-Hao Kuo, Kezhong Zhang, Hien M. Nguyen
Alzheimer’s disease (AD) is the most common form of dementia, marked by progressive brain degeneration and cognitive decline. A major pathological feature of AD is the accumulation of hyperphosphorylated tau (p-tau) in the form of neurofibrillary tangles (NFTs), which leads to neuronal death and neurodegeneration. P-tau also induces endoplasmic reticulum (ER) stress and activates the unfolded protein response, causing inflammation and apoptosis. Additionally, p-tau spreads in the brain through interactions with heparan sulfate (HS) proteoglycans, promoting aggregation and internalization. Targeting the tau–HS interaction offers a potential therapeutic strategy for AD. We present a novel HS mimetic with a lipophilic oleanolic acid linker and a sulfated trisaccharide, which shows strong cytoprotective effects against p-tau. Moreover, this compound alleviates p-tau-induced ER stress and inflammation. Molecular docking studies indicate that the conjugation of oleanolic acid enhances binding between the ligand and tau protofilament cores, facilitating protective interactions. These findings provide a foundation for the development of novel HS mimetics, enabling further investigation of tau-HS interactions in AD and other tauopathies.
{"title":"Effects of Heparan Sulfate Trisaccharide Containing Oleanolic Acid in Attenuating Hyperphosphorylated Tau-Induced Cell Dysfunction Associated with Alzheimer’s Disease","authors":"Sanyong Zhu, Zhenfeng Song, April Sweet Tapayan, Kartikey Singh, Kuang-Wei Wang, Hsiao-Tien Chien Hagar, Jicheng Zhang, Hyunbae Kim, Patty Thepsuwan, Min-Hao Kuo, Kezhong Zhang, Hien M. Nguyen","doi":"10.1021/acs.jmedchem.4c02563","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.4c02563","url":null,"abstract":"Alzheimer’s disease (AD) is the most common form of dementia, marked by progressive brain degeneration and cognitive decline. A major pathological feature of AD is the accumulation of hyperphosphorylated tau (p-tau) in the form of neurofibrillary tangles (NFTs), which leads to neuronal death and neurodegeneration. P-tau also induces endoplasmic reticulum (ER) stress and activates the unfolded protein response, causing inflammation and apoptosis. Additionally, p-tau spreads in the brain through interactions with heparan sulfate (HS) proteoglycans, promoting aggregation and internalization. Targeting the tau–HS interaction offers a potential therapeutic strategy for AD. We present a novel HS mimetic with a lipophilic oleanolic acid linker and a sulfated trisaccharide, which shows strong cytoprotective effects against p-tau. Moreover, this compound alleviates p-tau-induced ER stress and inflammation. Molecular docking studies indicate that the conjugation of oleanolic acid enhances binding between the ligand and tau protofilament cores, facilitating protective interactions. These findings provide a foundation for the development of novel HS mimetics, enabling further investigation of tau-HS interactions in AD and other tauopathies.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"52 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2025-01-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143020379","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 : 2025-01-22DOI: 10.1021/acs.jmedchem.5c00108
Adam G. Bond, Conner Craigon, Kwok-Ho Chan, Andrea Testa, Athanasios Karapetsas, Rotimi Fasimoye, Thomas Macartney, J. Julian Blow, Dario R. Alessi, Alessio Ciulli
It has come to our attention that two of the Western blot panels in Figure 5, namely, the “Brd4 short” lanes for ET-OMZ1 (<b>23</b>) and ET-OARV-771 (<b>25</b>) were the same. This arose as a result of an honest mistake when choosing panels used from the corresponding uncropped blots. This is clear from the relevant Supplemental Figure (Figure S7, page 16 in the Supporting Information), which shows all the full-length uncropped blots that were used to prepare the final Figure 5. The figure has been corrected and shows the correct panel corresponding to “Brd4 short” for ET-OMZ1 (<b>23</b>). The panel corresponding to “Brd4 short” for compound ET-OARV-771 (<b>25</b>) was correct and thus did not require changes. Having recognized this issue, we decided to go over ALL the material again and found a few other minor issues. We discovered that the “Brd4 short” panel for ME-OARV-771 (<b>24</b>) was also incorrectly chosen from the corresponding uncropped blot (see the same relevant Supplemental Figure S7, on page 16 in the Supporting Information). This has now been corrected. We have also found that the “tubulin” panels for ET-MZ1 (<b>19</b>), ME-ARV-771 (<b>20</b>) and ET-ARV-771 (<b>21</b>) were incorrectly cropped to show 8 lanes instead of the 7 in question, keeping an additional irrelevant lane on the far right of the panels. We have now recropped these panels to remove this lane. Figure 5 with the corrected panels is shown above. The data analysis and conclusions are not affected by these mistakes. Page 15496 (middle of right column). The identity of the template backbone of the BromoTag vector donor was incorrectly quoted as “pcDNA5”. The correct vector is “pMK-RQ” as follows. HEK293 cells were transfected using a Fugene HD transfection reagent (Madison, Wisconsin, United States) or lipofectamine 2000 (Madison, Wisconsin, United States) simultaneously with three custom vectors including a px335 vector (Addgene) containing a U6-snRNA and Cas9D10A expression cassette, a pBABED vector (MRC PPU, Dundee University) harboring another U6-sgRNA and puromycin expression cassette, and finally a pMK-RQ vector containing an eGFP-P2A-BromoTag-Brd2 donor knock-in sequence. Page 15498 (bottom of left column). The size of the tissue culture plate used was incorrectly quoted as “100 cm”. The correct size is “10 cm” as follows. CRISPR-modified BromoTag-Brd2 HEK293 cells (5 × 10<sup>6</sup>) were seeded on a 10 cm plate 24 h before treatment. We have revised the Supporting Information to add text to clarify the number of biological replicates (<i>n</i>) that were performed for each experiment. We have now also realized that the “Brd4 antibody” panel for PROTAC AGB1 (<b>46</b>) at the top right of Supplementary Figure 9 on page 24 in the Supporting Information (and the corresponding tubulin loading control) was from a different biological replicate of the same experiment than the one chosen in the corresponding main text figure (Figure 6, on page 15489). This has no
{"title":"Correction to “Development of BromoTag: A “Bump-and-Hole”–PROTAC System To Induce Potent, Rapid, and Selective Degradation of Tagged Target Proteins”","authors":"Adam G. Bond, Conner Craigon, Kwok-Ho Chan, Andrea Testa, Athanasios Karapetsas, Rotimi Fasimoye, Thomas Macartney, J. Julian Blow, Dario R. Alessi, Alessio Ciulli","doi":"10.1021/acs.jmedchem.5c00108","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.5c00108","url":null,"abstract":"It has come to our attention that two of the Western blot panels in Figure 5, namely, the “Brd4 short” lanes for ET-OMZ1 (<b>23</b>) and ET-OARV-771 (<b>25</b>) were the same. This arose as a result of an honest mistake when choosing panels used from the corresponding uncropped blots. This is clear from the relevant Supplemental Figure (Figure S7, page 16 in the Supporting Information), which shows all the full-length uncropped blots that were used to prepare the final Figure 5. The figure has been corrected and shows the correct panel corresponding to “Brd4 short” for ET-OMZ1 (<b>23</b>). The panel corresponding to “Brd4 short” for compound ET-OARV-771 (<b>25</b>) was correct and thus did not require changes. Having recognized this issue, we decided to go over ALL the material again and found a few other minor issues. We discovered that the “Brd4 short” panel for ME-OARV-771 (<b>24</b>) was also incorrectly chosen from the corresponding uncropped blot (see the same relevant Supplemental Figure S7, on page 16 in the Supporting Information). This has now been corrected. We have also found that the “tubulin” panels for ET-MZ1 (<b>19</b>), ME-ARV-771 (<b>20</b>) and ET-ARV-771 (<b>21</b>) were incorrectly cropped to show 8 lanes instead of the 7 in question, keeping an additional irrelevant lane on the far right of the panels. We have now recropped these panels to remove this lane. Figure 5 with the corrected panels is shown above. The data analysis and conclusions are not affected by these mistakes. Page 15496 (middle of right column). The identity of the template backbone of the BromoTag vector donor was incorrectly quoted as “pcDNA5”. The correct vector is “pMK-RQ” as follows. HEK293 cells were transfected using a Fugene HD transfection reagent (Madison, Wisconsin, United States) or lipofectamine 2000 (Madison, Wisconsin, United States) simultaneously with three custom vectors including a px335 vector (Addgene) containing a U6-snRNA and Cas9D10A expression cassette, a pBABED vector (MRC PPU, Dundee University) harboring another U6-sgRNA and puromycin expression cassette, and finally a pMK-RQ vector containing an eGFP-P2A-BromoTag-Brd2 donor knock-in sequence. Page 15498 (bottom of left column). The size of the tissue culture plate used was incorrectly quoted as “100 cm”. The correct size is “10 cm” as follows. CRISPR-modified BromoTag-Brd2 HEK293 cells (5 × 10<sup>6</sup>) were seeded on a 10 cm plate 24 h before treatment. We have revised the Supporting Information to add text to clarify the number of biological replicates (<i>n</i>) that were performed for each experiment. We have now also realized that the “Brd4 antibody” panel for PROTAC AGB1 (<b>46</b>) at the top right of Supplementary Figure 9 on page 24 in the Supporting Information (and the corresponding tubulin loading control) was from a different biological replicate of the same experiment than the one chosen in the corresponding main text figure (Figure 6, on page 15489). This has no","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"88 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2025-01-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142992052","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 : 2025-01-22DOI: 10.1021/acs.jmedchem.4c02472
Tom Schulz, Rajesh Gontla, Alina Teuber, Maria Beerbaum, Benjamin S. Fletcher, Thomas Mühlenberg, Helena Kaitsiotou, Julia Hardick, Kirujan Jeyakumar, Marina Keul, Matthias P. Müller, Sonja Sievers, Sebastian Bauer, Daniel Rauh
Gastrointestinal stromal tumors (GIST), driven by KIT and PDGFRA mutations, are the most common mesenchymal tumors of the gastrointestinal tract. Although tyrosine kinase inhibitors (TKIs) have advanced treatment, resistance mutations and off-target toxicity limit their efficacy. This study develops covalent TKIs targeting drug-resistant GIST through structure-based design, synthesis, and biological evaluation. SAR studies provided key insights into mutant KIT and PDGFRA interactions, and the first crystal structure of PDGFRA bound to a covalent inhibitor is reported. These findings highlight the promise of covalent inhibitors for overcoming resistance and advancing safer, more effective therapies for advanced GIST.
{"title":"Design, Synthesis, and SAR of Covalent KIT and PDGFRA Inhibitors─Exploring Their Potential in Targeting GIST","authors":"Tom Schulz, Rajesh Gontla, Alina Teuber, Maria Beerbaum, Benjamin S. Fletcher, Thomas Mühlenberg, Helena Kaitsiotou, Julia Hardick, Kirujan Jeyakumar, Marina Keul, Matthias P. Müller, Sonja Sievers, Sebastian Bauer, Daniel Rauh","doi":"10.1021/acs.jmedchem.4c02472","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.4c02472","url":null,"abstract":"Gastrointestinal stromal tumors (GIST), driven by KIT and PDGFRA mutations, are the most common mesenchymal tumors of the gastrointestinal tract. Although tyrosine kinase inhibitors (TKIs) have advanced treatment, resistance mutations and off-target toxicity limit their efficacy. This study develops covalent TKIs targeting drug-resistant GIST through structure-based design, synthesis, and biological evaluation. SAR studies provided key insights into mutant KIT and PDGFRA interactions, and the first crystal structure of PDGFRA bound to a covalent inhibitor is reported. These findings highlight the promise of covalent inhibitors for overcoming resistance and advancing safer, more effective therapies for advanced GIST.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"26 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2025-01-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142992612","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 : 2025-01-22DOI: 10.1021/acs.jmedchem.4c01822
Carlo Walz, Moritz Spiske, Magnus Walter, Benjamin-Luca Keller, Mario Mezler, Carolin Hoft, Frauke Pohlki, Stella Vukelić, Felix Hausch
In recent years, rationally designed macrocycles have emerged as promising therapeutic modalities for challenging drug targets. Macrocycles can improve affinity, selectivity, and pharmacokinetic (PK) parameters, possibly via providing semirigid, preorganized scaffolds. Nevertheless, how macrocyclization affects PK-relevant properties is still poorly understood. To address this question, we systematically generated and compared 15 matched molecular pairs of macrocycles and structurally similar linear analogs. We found that macrocyclization substantially improves kinetic solubility while not impairing the other measured parameters. We hypothesize that this could arise from “chameleonicity,” which was previously reported for large, natural-product-derived macrocycles. Our results show that the improvement of kinetic solubility is an underappreciated aspect of macrocycles that may facilitate formulation strategies compared to linear analogs to improve bioavailability.
{"title":"Macrocyclization as a Strategy for Kinetic Solubility Improvement: A Comparative Analysis of Matched Molecular Pairs","authors":"Carlo Walz, Moritz Spiske, Magnus Walter, Benjamin-Luca Keller, Mario Mezler, Carolin Hoft, Frauke Pohlki, Stella Vukelić, Felix Hausch","doi":"10.1021/acs.jmedchem.4c01822","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.4c01822","url":null,"abstract":"In recent years, rationally designed macrocycles have emerged as promising therapeutic modalities for challenging drug targets. Macrocycles can improve affinity, selectivity, and pharmacokinetic (PK) parameters, possibly via providing semirigid, preorganized scaffolds. Nevertheless, how macrocyclization affects PK-relevant properties is still poorly understood. To address this question, we systematically generated and compared 15 matched molecular pairs of macrocycles and structurally similar linear analogs. We found that macrocyclization substantially improves kinetic solubility while not impairing the other measured parameters. We hypothesize that this could arise from “chameleonicity,” which was previously reported for large, natural-product-derived macrocycles. Our results show that the improvement of kinetic solubility is an underappreciated aspect of macrocycles that may facilitate formulation strategies compared to linear analogs to improve bioavailability.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"32 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2025-01-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142992050","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}
Over the years, numerous ligand-based organotin(IV) Schiff base compounds have shown remarkable cytotoxicity and anticancer activities, but their clinical use is restricted by systemic toxicity, prompting the search for targeted therapies. Targeted delivery can be enhanced by exploiting the inherent characteristics of cancer cells such as glutamine addiction, which is essential to support cellular biosynthesis and cell growth to sustain aberrant proliferation. Our previous study revealed glutamine-conjugated organotin(IV) compounds have strong DNA/protein affinities, favorable in silico ADME profiles, and significant antiproliferative activity. In this study, these compounds demonstrated significant cytotoxicity against human colon carcinoma and adenocarcinoma cell lines via the induction of cell cycle arrest and apoptosis. In DMH/DSS-induced experimental colon carcinogenesis, these compounds reduced tumor burden and volume and inhibited cell proliferation and induced apoptosis, with minimal toxicity. Tissue distribution studies revealed selective accumulation in the colon. These findings support their potential as chemotherapeutic candidates for colon cancer.
{"title":"Evaluation of Anticancer Activity of Novel and Tumor-Targeted Glutamine-Conjugated Organotin(IV) Compounds in Colorectal Cancer─An In Vitro and In Vivo Study","authors":"Shagun Sharma, Varinder Kaur, Pratibha Duhan, Raghubir Singh, Navneet Agnihotri","doi":"10.1021/acs.jmedchem.4c01728","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.4c01728","url":null,"abstract":"Over the years, numerous ligand-based organotin(IV) Schiff base compounds have shown remarkable cytotoxicity and anticancer activities, but their clinical use is restricted by systemic toxicity, prompting the search for targeted therapies. Targeted delivery can be enhanced by exploiting the inherent characteristics of cancer cells such as glutamine addiction, which is essential to support cellular biosynthesis and cell growth to sustain aberrant proliferation. Our previous study revealed glutamine-conjugated organotin(IV) compounds have strong DNA/protein affinities, favorable in silico ADME profiles, and significant antiproliferative activity. In this study, these compounds demonstrated significant cytotoxicity against human colon carcinoma and adenocarcinoma cell lines via the induction of cell cycle arrest and apoptosis. In DMH/DSS-induced experimental colon carcinogenesis, these compounds reduced tumor burden and volume and inhibited cell proliferation and induced apoptosis, with minimal toxicity. Tissue distribution studies revealed selective accumulation in the colon. These findings support their potential as chemotherapeutic candidates for colon cancer.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"74 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2025-01-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142991018","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 : 2025-01-21DOI: 10.1021/acs.jmedchem.4c02634
Sai Yang, Xiaowen Gu, Lei Chen, Weixing Zhu
Synthetic lethality offers a robust strategy for discovering the next generation of precision medicine therapies tailored for molecularly defined patient populations. MAT2A inhibition is synthetically lethal in several cancers that exhibit a homozygous deletion of S-methyl-5′-thioadenosine phosphorylase (MTAP). Herein, we report the identification of novel MAT2A inhibitors featuring a spiral ring to circumvent the C–N atropisomeric chirality utilizing structure-based drug design. The Hit compound 9 exhibited high potency in enzymatic activity (IC50 = 7 nM) and in HCT-116 MTAP(−/−) cell potency (IC50 = 17 nM). Further optimization has led to the identification of two new lead compounds: a brain-penetrant compound, 29–1, and a potent but limited brain-penetrant compound, 39. Both of these lead compounds demonstrate increased plasma drug exposure and exhibit significant efficacy in xenograft models that are depleted of MTAP. We hope that identifying a brain-penetrant MAT2A inhibitor will create new opportunities to explore the potential therapeutic effects of S-adenosylmethionine modulation in the central nervous system.
{"title":"Discovery of Novel Spirocyclic MAT2A Inhibitors Demonstrating High In Vivo Efficacy in MTAP-Null Xenograft Models","authors":"Sai Yang, Xiaowen Gu, Lei Chen, Weixing Zhu","doi":"10.1021/acs.jmedchem.4c02634","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.4c02634","url":null,"abstract":"Synthetic lethality offers a robust strategy for discovering the next generation of precision medicine therapies tailored for molecularly defined patient populations. MAT2A inhibition is synthetically lethal in several cancers that exhibit a homozygous deletion of <i>S</i>-methyl-5′-thioadenosine phosphorylase (MTAP). Herein, we report the identification of novel MAT2A inhibitors featuring a spiral ring to circumvent the C–N atropisomeric chirality utilizing structure-based drug design. The Hit compound <b>9</b> exhibited high potency in enzymatic activity (IC<sub>50</sub> = 7 nM) and in HCT-116 MTAP<sup>(−/−)</sup> cell potency (IC<sub>50</sub> = 17 nM). Further optimization has led to the identification of two new lead compounds: a brain-penetrant compound, <b>29–1</b>, and a potent but limited brain-penetrant compound, <b>39</b>. Both of these lead compounds demonstrate increased plasma drug exposure and exhibit significant efficacy in xenograft models that are depleted of MTAP. We hope that identifying a brain-penetrant MAT2A inhibitor will create new opportunities to explore the potential therapeutic effects of <i>S</i>-adenosylmethionine modulation in the central nervous system.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"71 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2025-01-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142991020","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}
Since decades after temozolomide was approved, no effective drugs have been developed. Undoubtedly, blood–brain barrier (BBB) penetration is a severe issue that should be overcome in glioblastoma multiforme (GBM) drug development. In this research, we were inspired by linezolid through structural modification with several bioactive moieties to achieve the desired brain delivery. The results indicated that the histone deacetylase modification, referred to as compound 1, demonstrated promising cytotoxic effects in various brain tumor cell lines. Further comprehensive mechanism studies indicated that compound 1 induced acetylation, leading to DNA double-strand breaks, and induced the ubiquitination of RAD51, disrupting the DNA repair process. Furthermore, compound 1 also exhibited dramatic improvement in the orthotopic GBM mouse model, demonstrating its efficacy and satisfying BBB penetration. Therefore, the reported compound 1, provided with an independent therapeutic pathway, satisfying elongation in survival and tumor size reduction, and the ability to penetrate the BBB, was potent to achieve further development.
{"title":"Repurposing Linezolid in Conjunction with Histone Deacetylase Inhibitor Access in the Realm of Glioblastoma Therapies","authors":"I-Chung Chen, Hong-Yi Lin, Zheng-Yang Liu, Wei-Jie Cheng, Tzu-Yi Yeh, Wen-Bin Yang, Hoang Yen Tran, Mei-Jung Lai, Chung-Han Wang, Tzu-Yuan Kao, Chia-Yang Hung, Ya-Lin Huang, Ke-Chi Liou, Chien-Ming Hsieh, Tsung-I Hsu, Jing-Ping Liou","doi":"10.1021/acs.jmedchem.4c02086","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.4c02086","url":null,"abstract":"Since decades after temozolomide was approved, no effective drugs have been developed. Undoubtedly, blood–brain barrier (BBB) penetration is a severe issue that should be overcome in glioblastoma multiforme (GBM) drug development. In this research, we were inspired by linezolid through structural modification with several bioactive moieties to achieve the desired brain delivery. The results indicated that the histone deacetylase modification, referred to as compound <b>1</b>, demonstrated promising cytotoxic effects in various brain tumor cell lines. Further comprehensive mechanism studies indicated that compound <b>1</b> induced acetylation, leading to DNA double-strand breaks, and induced the ubiquitination of RAD51, disrupting the DNA repair process. Furthermore, compound <b>1</b> also exhibited dramatic improvement in the orthotopic GBM mouse model, demonstrating its efficacy and satisfying BBB penetration. Therefore, the reported compound <b>1</b>, provided with an independent therapeutic pathway, satisfying elongation in survival and tumor size reduction, and the ability to penetrate the BBB, was potent to achieve further development.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"9 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2025-01-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142991019","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 : 2025-01-21DOI: 10.1021/acs.jmedchem.4c00691
Abdul Mannan Baig, Sandy Rosko, Beate Jaeger, Joachim Gerlach
In addition to the conventional symptoms reported for COVID-19, it is becoming increasingly clear that patients with long COVID are exhibiting new symptoms due to the emergence of autoantibodies against G-protein-coupled receptors, among which human muscarinic cholinergic receptors (CHRMs) have been prominently reported. With a chronic condition such as long COVID, additional symptoms caused by anti-CHRM autoantibodies (AAbs) have proven to be an added burden on these patients. The origins of these AAbs, their interactions with, and effects on the function of neural and non-neural cells within the nervous system have remained unknown. Furthermore, the specific symptom complex to which they contribute has not been clearly understood. In this context, we address these issues here and suggest methods to combat the autoantibodies that contribute to neurological symptoms in long COVID.
{"title":"Strategic Inhibition of CHRM Autoantibodies: Molecular Insights and Therapeutic Potentials in Long COVID","authors":"Abdul Mannan Baig, Sandy Rosko, Beate Jaeger, Joachim Gerlach","doi":"10.1021/acs.jmedchem.4c00691","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.4c00691","url":null,"abstract":"In addition to the conventional symptoms reported for COVID-19, it is becoming increasingly clear that patients with long COVID are exhibiting new symptoms due to the emergence of autoantibodies against G-protein-coupled receptors, among which human muscarinic cholinergic receptors (CHRMs) have been prominently reported. With a chronic condition such as long COVID, additional symptoms caused by anti-CHRM autoantibodies (AAbs) have proven to be an added burden on these patients. The origins of these AAbs, their interactions with, and effects on the function of neural and non-neural cells within the nervous system have remained unknown. Furthermore, the specific symptom complex to which they contribute has not been clearly understood. In this context, we address these issues here and suggest methods to combat the autoantibodies that contribute to neurological symptoms in long COVID.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"46 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2025-01-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142991017","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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