Pub Date : 2024-05-20DOI: 10.1021/acsmedchemlett.4c00125
Sana Chaudhry, Jesus R. Castro, Tulasigeri M. Totiger, Jumana Afaghani, Rabia Khurshid, Miah Nicholls, Ziming Zhang, Stephan C. Schürer, Ashish Shah, Justin Taylor* and Yangbo Feng*,
STK17A is a novel uncharacterized member of the death-associated protein family of serine and threonine kinases. Overexpression of STK17A is observed in many cancers. We identified a lead compound that is based on a quinazoline core. Optimizations of the lead compound led to the discovery of potent and selective STK17A/B inhibitors with drug-like properties and oral bioavailability. Compound 9 had an STK17A inhibitory IC50 of 23 nM. Based on profiling studies against two wild-type kinase panels (375 and 398 kinases, respectively), compound 9 had strong inhibition of both STK17A and STK17B but moderate off-target inhibition only for AAK1, MYLK4, and NEK3/5. In addition, compound 9 had good oral bioavailability, paving the way for in vivo studies against various cancers.
{"title":"Potent, Selective, and Orally Bioavailable Quinazoline-Based STK17A/B Dual Inhibitors","authors":"Sana Chaudhry, Jesus R. Castro, Tulasigeri M. Totiger, Jumana Afaghani, Rabia Khurshid, Miah Nicholls, Ziming Zhang, Stephan C. Schürer, Ashish Shah, Justin Taylor* and Yangbo Feng*, ","doi":"10.1021/acsmedchemlett.4c00125","DOIUrl":"10.1021/acsmedchemlett.4c00125","url":null,"abstract":"<p >STK17A is a novel uncharacterized member of the death-associated protein family of serine and threonine kinases. Overexpression of STK17A is observed in many cancers. We identified a lead compound that is based on a quinazoline core. Optimizations of the lead compound led to the discovery of potent and selective STK17A/B inhibitors with drug-like properties and oral bioavailability. Compound <b>9</b> had an STK17A inhibitory IC<sub>50</sub> of 23 nM. Based on profiling studies against two wild-type kinase panels (375 and 398 kinases, respectively), compound <b>9</b> had strong inhibition of both STK17A and STK17B but moderate off-target inhibition only for AAK1, MYLK4, and NEK3/5. In addition, compound <b>9</b> had good oral bioavailability, paving the way for in vivo studies against various cancers.</p>","PeriodicalId":20,"journal":{"name":"ACS Medicinal Chemistry Letters","volume":null,"pages":null},"PeriodicalIF":4.2,"publicationDate":"2024-05-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141120664","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-05-20DOI: 10.1021/acsmedchemlett.4c00113
Simon C. C. Lucas*, J. Henry Blackwell, Ulf Börjesson, David Hargreaves, Alexander G. Milbradt, Samiyah Ahmed, Mark J. Bostock, Carine Guerot, Andrea Gohlke, Olaf Kinzel, Michelle L. Lamb, Nidhal Selmi, Christopher J. Stubbs, Nancy Su, Qibin Su, Haiou Luo, Ting Xiong, Xiaoqian Zuo, Sana Bazzaz, Corey Bienstock, Paolo A. Centrella, Kyle E. Denton, Diana Gikunju, Marie-Aude Guié, John P. Guilinger, Christopher Hupp, Anthony D. Keefe, Takashi Satoh, Ying Zhang and Emma L. Rivers,
Bfl-1 is overexpressed in both hematological and solid tumors; therefore, inhibitors of Bfl-1 are highly desirable. A DNA-encoded chemical library (DEL) screen against Bfl-1 identified the first known reversible covalent small-molecule ligand for Bfl-1. The binding was validated through biophysical and biochemical techniques, which confirmed the reversible covalent mechanism of action and pointed to binding through Cys55. This represented the first identification of a cyano-acrylamide reversible covalent compound from a DEL screen and highlights further opportunities for covalent drug discovery through DEL screening. A 10-fold improvement in potency was achieved through a systematic SAR exploration of the hit. The more potent analogue compound 13 was successfully cocrystallized in Bfl-1, revealing the binding mode and providing further evidence of a covalent interaction with Cys55.
Bfl-1 在血液肿瘤和实体瘤中都有过表达,因此,Bfl-1 的抑制剂是非常理想的。针对 Bfl-1 的 DNA 编码化学文库(DEL)筛选发现了首个已知的 Bfl-1 可逆共价小分子配体。这种结合通过生物物理和生物化学技术进行了验证,确认了可逆共价作用机制,并指出是通过 Cys55 结合的。这是首次从 DEL 筛选中发现氰基丙烯酰胺可逆共价化合物,并凸显了通过 DEL 筛选发现共价药物的更多机会。通过对命中化合物进行系统的 SAR 探索,药效提高了 10 倍。药效更强的类似物化合物 13 成功在 Bfl-1 中结晶,揭示了其结合模式,并提供了与 Cys55 发生共价作用的进一步证据。
{"title":"Identification and Evaluation of Reversible Covalent Binders to Cys55 of Bfl-1 from a DNA-Encoded Chemical Library Screen","authors":"Simon C. C. Lucas*, J. Henry Blackwell, Ulf Börjesson, David Hargreaves, Alexander G. Milbradt, Samiyah Ahmed, Mark J. Bostock, Carine Guerot, Andrea Gohlke, Olaf Kinzel, Michelle L. Lamb, Nidhal Selmi, Christopher J. Stubbs, Nancy Su, Qibin Su, Haiou Luo, Ting Xiong, Xiaoqian Zuo, Sana Bazzaz, Corey Bienstock, Paolo A. Centrella, Kyle E. Denton, Diana Gikunju, Marie-Aude Guié, John P. Guilinger, Christopher Hupp, Anthony D. Keefe, Takashi Satoh, Ying Zhang and Emma L. Rivers, ","doi":"10.1021/acsmedchemlett.4c00113","DOIUrl":"10.1021/acsmedchemlett.4c00113","url":null,"abstract":"<p >Bfl-1 is overexpressed in both hematological and solid tumors; therefore, inhibitors of Bfl-1 are highly desirable. A DNA-encoded chemical library (DEL) screen against Bfl-1 identified the first known reversible covalent small-molecule ligand for Bfl-1. The binding was validated through biophysical and biochemical techniques, which confirmed the reversible covalent mechanism of action and pointed to binding through Cys55. This represented the first identification of a cyano-acrylamide reversible covalent compound from a DEL screen and highlights further opportunities for covalent drug discovery through DEL screening. A 10-fold improvement in potency was achieved through a systematic SAR exploration of the hit. The more potent analogue compound <b>13</b> was successfully cocrystallized in Bfl-1, revealing the binding mode and providing further evidence of a covalent interaction with Cys55.</p>","PeriodicalId":20,"journal":{"name":"ACS Medicinal Chemistry Letters","volume":null,"pages":null},"PeriodicalIF":4.2,"publicationDate":"2024-05-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141123255","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-05-20DOI: 10.1021/acsmedchemlett.4c00146
Lauren R. Blankenship, Kai S. Yang, Veerabhadra R. Vulupala, Yugendar R. Alugubelli, Kaustav Khatua, Demonta Coleman, Xinyu R. Ma, Banumathi Sankaran, Chia-Chuan D. Cho, Yuying Ma, Benjamin W. Neuman, Shiqing Xu* and Wenshe Ray Liu*,
The main protease (MPro) of SARS-CoV-2 is crucial for the virus’s replication and pathogenicity. Its active site is characterized by four distinct pockets (S1, S2, S4, and S1–3′) and a solvent-exposed S3 site for accommodating a protein substrate. During X-ray crystallographic analyses of MPro bound with dipeptide inhibitors containing a flexible N-terminal group, we often observed an unexpected binding mode. Contrary to the anticipated engagement with the deeper S4 pocket, the N-terminal group frequently assumed a twisted conformation, positioning it for interactions with the S3 site and the inhibitor component bound at the S1 pocket. Capitalizing on this observation, we engineered novel inhibitors to engage both S3 and S4 sites or to adopt a rigid conformation for selective S3 site binding. Several new inhibitors demonstrated high efficacy in MPro inhibition. Our findings underscore the importance of the S3 site’s unique interactions in the design of future MPro inhibitors as potential COVID-19 therapeutics.
{"title":"SARS-CoV-2 Main Protease Inhibitors That Leverage Unique Interactions with the Solvent Exposed S3 Site of the Enzyme","authors":"Lauren R. Blankenship, Kai S. Yang, Veerabhadra R. Vulupala, Yugendar R. Alugubelli, Kaustav Khatua, Demonta Coleman, Xinyu R. Ma, Banumathi Sankaran, Chia-Chuan D. Cho, Yuying Ma, Benjamin W. Neuman, Shiqing Xu* and Wenshe Ray Liu*, ","doi":"10.1021/acsmedchemlett.4c00146","DOIUrl":"10.1021/acsmedchemlett.4c00146","url":null,"abstract":"<p >The main protease (M<sup>Pro</sup>) of SARS-CoV-2 is crucial for the virus’s replication and pathogenicity. Its active site is characterized by four distinct pockets (S1, S2, S4, and S1–3′) and a solvent-exposed S3 site for accommodating a protein substrate. During X-ray crystallographic analyses of M<sup>Pro</sup> bound with dipeptide inhibitors containing a flexible <i>N</i>-terminal group, we often observed an unexpected binding mode. Contrary to the anticipated engagement with the deeper S4 pocket, the <i>N</i>-terminal group frequently assumed a twisted conformation, positioning it for interactions with the S3 site and the inhibitor component bound at the S1 pocket. Capitalizing on this observation, we engineered novel inhibitors to engage both S3 and S4 sites or to adopt a rigid conformation for selective S3 site binding. Several new inhibitors demonstrated high efficacy in M<sup>Pro</sup> inhibition. Our findings underscore the importance of the S3 site’s unique interactions in the design of future M<sup>Pro</sup> inhibitors as potential COVID-19 therapeutics.</p>","PeriodicalId":20,"journal":{"name":"ACS Medicinal Chemistry Letters","volume":null,"pages":null},"PeriodicalIF":4.2,"publicationDate":"2024-05-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/epdf/10.1021/acsmedchemlett.4c00146","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141122011","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-05-20DOI: 10.1021/acsmedchemlett.4c00114
Rukaiyya T. Girase, Iqrar Ahmad, Jong Min Oh, Bijo Mathew, Siva K. Vagolu, Tone Tønjum, Dharmarajan Sriram, Jyothi Kumari, Nisheeth C. Desai, Yogesh Agrawal, Hoon Kim* and Harun M. Patel*,
Serotonergic toxicity due to MAO enzyme inhibition is a significant concern when using linezolid to treat MDR-TB. To address this issue, we designed linezolid bioisosteres with a modified acetamidomethyl side chain at the C-5 position of the oxazolidine ring to balance activity and reduce toxicity. Among these bioisosteres, R7 emerged as a promising candidate, demonstrating greater effectiveness against M. tuberculosis (Mtb) H37Rv cells with an MIC of 2.01 μM compared to linezolid (MIC = 2.31 μM). Bioisostere R7 also exhibited remarkable activity (MIC50) against drug-resistant Mtb clinical isolates, with values of 0.14 μM (INHR, inhA+), 0.53 μM (INHR, katG+), 0.24 μM (RIFR, rpoB+), and 0.92 μM (INHR INHR, MDR). Importantly, it was >6.52 times less toxic as compared to the linezolid toward the MAO-A and >64 times toward the MAO-B enzyme, signifying a substantial improvement in its drug safety profile.
{"title":"Design and Synthesis of the Linezolid Bioisosteres to Resolve the Serotonergic Toxicity Associated with Linezolid","authors":"Rukaiyya T. Girase, Iqrar Ahmad, Jong Min Oh, Bijo Mathew, Siva K. Vagolu, Tone Tønjum, Dharmarajan Sriram, Jyothi Kumari, Nisheeth C. Desai, Yogesh Agrawal, Hoon Kim* and Harun M. Patel*, ","doi":"10.1021/acsmedchemlett.4c00114","DOIUrl":"10.1021/acsmedchemlett.4c00114","url":null,"abstract":"<p >Serotonergic toxicity due to MAO enzyme inhibition is a significant concern when using linezolid to treat MDR-TB. To address this issue, we designed linezolid bioisosteres with a modified acetamidomethyl side chain at the C-5 position of the oxazolidine ring to balance activity and reduce toxicity. Among these bioisosteres, <b>R7</b> emerged as a promising candidate, demonstrating greater effectiveness against <i>M. tuberculosis</i> (<i>Mtb</i>) H<sub>37</sub>Rv cells with an MIC of 2.01 μM compared to linezolid (MIC = 2.31 μM). Bioisostere <b>R7</b> also exhibited remarkable activity (MIC<sub>50</sub>) against drug-resistant <i>Mtb</i> clinical isolates, with values of 0.14 μM (INH<sup>R</sup>, <i>inhA+</i>), 0.53 μM (INH<sup>R</sup>, <i>katG+</i>), 0.24 μM (RIF<sup>R</sup>, <i>rpoB+</i>), and 0.92 μM (INH<sup>R</sup> INH<sup>R</sup>, MDR). Importantly, it was >6.52 times less toxic as compared to the linezolid toward the MAO-A and >64 times toward the MAO-B enzyme, signifying a substantial improvement in its drug safety profile.</p>","PeriodicalId":20,"journal":{"name":"ACS Medicinal Chemistry Letters","volume":null,"pages":null},"PeriodicalIF":4.2,"publicationDate":"2024-05-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141120939","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-05-20DOI: 10.1021/acsmedchemlett.3c00532
Demeng Sun, Bo Wang, Yanmei Jiang, Zuo Kong, Mengxue Mu, Changhuan Yang, Jingbo Tan and Yun Hu*,
In this study, a series of N-phenyl-2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamide derivatives were designed, synthesized, and evaluated for their inhibitory activities against human MAO-B (hMAO-B). The structure–activity relationship (SAR) was investigated and summarized. Compound 1l (N-(3,4-dichlorophenyl)-2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamide) showed the most potent inhibitory activity with an IC50 value of 0.0083 μM and the selectivity index (IC50 (hMAO-A)/IC50 (hMAO-B)) was >4819. Kinetics and reversibility studies confirmed that compound 1l acted as a competitive and reversible inhibitor of hMAO-B. Molecular docking studies revealed the enzyme–inhibitor interactions, and the rationale was provided. Additionally, compound 1l could effectively inhibit the release of NO, TNF-α, and IL-1β in both LPS- and Aβ1–42-stimulated BV2 cells and attenuate the cytotoxicity induced by Aβ1–42. Since compound 1l exhibited low neurotoxicity, we believe that the hit compound with dual activities of inhibiting MAO-B and antineuroinflammation could be further investigated as a novel potential lead for future studies in vivo.
{"title":"Benzodioxane Carboxamide Derivatives As Novel Monoamine Oxidase B Inhibitors with Antineuroinflammatory Activity","authors":"Demeng Sun, Bo Wang, Yanmei Jiang, Zuo Kong, Mengxue Mu, Changhuan Yang, Jingbo Tan and Yun Hu*, ","doi":"10.1021/acsmedchemlett.3c00532","DOIUrl":"10.1021/acsmedchemlett.3c00532","url":null,"abstract":"<p >In this study, a series of <i>N</i>-phenyl-2,3-dihydrobenzo[<i>b</i>][1,4]dioxine-6-carboxamide derivatives were designed, synthesized, and evaluated for their inhibitory activities against human MAO-B (<i>h</i>MAO-B). The structure–activity relationship (SAR) was investigated and summarized. Compound <b>1l</b> (<i>N</i>-(3,4-dichlorophenyl)-2,3-dihydrobenzo[<i>b</i>][1,4]dioxine-6-carboxamide) showed the most potent inhibitory activity with an IC<sub>50</sub> value of 0.0083 μM and the selectivity index (IC<sub>50</sub> (<i>h</i>MAO-A)/IC<sub>50</sub> (<i>h</i>MAO-B)) was >4819. Kinetics and reversibility studies confirmed that compound <b>1l</b> acted as a competitive and reversible inhibitor of <i>h</i>MAO-B. Molecular docking studies revealed the enzyme–inhibitor interactions, and the rationale was provided. Additionally, compound <b>1l</b> could effectively inhibit the release of NO, TNF-α, and IL-1β in both LPS- and Aβ<sub>1–42</sub>-stimulated BV2 cells and attenuate the cytotoxicity induced by Aβ<sub>1–42</sub>. Since compound <b>1l</b> exhibited low neurotoxicity, we believe that the hit compound with dual activities of inhibiting MAO-B and antineuroinflammation could be further investigated as a novel potential lead for future studies in vivo.</p>","PeriodicalId":20,"journal":{"name":"ACS Medicinal Chemistry Letters","volume":null,"pages":null},"PeriodicalIF":4.2,"publicationDate":"2024-05-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141122464","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-05-16DOI: 10.1021/acsmedchemlett.4c00051
Ping Liu, Lin Wang, Ya Song, Hairun Pei* and Xueli Cao*,
In this study, potential inhibitors of Streptococcus mutans biofilm were screened from Lonicera japonica flos using semiflexible molecular docking. A total of 88 metabolites from L. japonica flos and 14 biofilm-related proteins of S. mutans were analyzed, and 25 compounds were initially screened out. Subsequently, 9 compounds with higher availability were subjected to experimental validation, confirming that 6 of them effectively inhibit the S. mutans biofilm formation. Notably, chlorogenic acid was found to potentially disrupt the GbpC protein, which plays a role in the sucrose-dependent adhesion pathway. Similarly, oleanolic acid appeared to impede the adhesin P1 protein involved in the sucrose-independent adhesion mechanism, corroborating the computational predictions. The results of this study provide essential insights for leveraging L. japonica flos in the creation of dental-care-related products and food items aimed at oral health.
{"title":"Virtual Screening of Inhibitors of Streptococcus mutans Biofilm from Lonicera japonica flos and Activity Validation","authors":"Ping Liu, Lin Wang, Ya Song, Hairun Pei* and Xueli Cao*, ","doi":"10.1021/acsmedchemlett.4c00051","DOIUrl":"10.1021/acsmedchemlett.4c00051","url":null,"abstract":"<p >In this study, potential inhibitors of <i>Streptococcus mutans</i> biofilm were screened from <i>Lonicera japonica flos</i> using semiflexible molecular docking. A total of 88 metabolites from <i>L. japonica flos</i> and 14 biofilm-related proteins of <i>S. mutans</i> were analyzed, and 25 compounds were initially screened out. Subsequently, 9 compounds with higher availability were subjected to experimental validation, confirming that 6 of them effectively inhibit the <i>S. mutans</i> biofilm formation. Notably, chlorogenic acid was found to potentially disrupt the GbpC protein, which plays a role in the sucrose-dependent adhesion pathway. Similarly, oleanolic acid appeared to impede the adhesin P1 protein involved in the sucrose-independent adhesion mechanism, corroborating the computational predictions. The results of this study provide essential insights for leveraging <i>L. japonica flos</i> in the creation of dental-care-related products and food items aimed at oral health.</p>","PeriodicalId":20,"journal":{"name":"ACS Medicinal Chemistry Letters","volume":null,"pages":null},"PeriodicalIF":4.2,"publicationDate":"2024-05-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140968919","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-05-16DOI: 10.1021/acsmedchemlett.4c00195
Ram W. Sabnis*,
Provided herein are novel HSD17B13 inhibitors, pharmaceutical compositions, use of such compounds in treating liver diseases, and processes for preparing such compounds.
{"title":"Novel HSD17B13 Inhibitors for Treating Liver Diseases","authors":"Ram W. Sabnis*, ","doi":"10.1021/acsmedchemlett.4c00195","DOIUrl":"10.1021/acsmedchemlett.4c00195","url":null,"abstract":"<p >Provided herein are novel HSD17B13 inhibitors, pharmaceutical compositions, use of such compounds in treating liver diseases, and processes for preparing such compounds.</p>","PeriodicalId":20,"journal":{"name":"ACS Medicinal Chemistry Letters","volume":null,"pages":null},"PeriodicalIF":4.2,"publicationDate":"2024-05-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140968501","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-05-16DOI: 10.1021/acsmedchemlett.4c00196
Ram W. Sabnis*,
Provided herein are novel tyrosine kinase 2 inhibitors, pharmaceutical compositions, use of such compounds in treating autoimmune and inflammatory diseases, and processes for preparing such compounds.
{"title":"Novel Tyrosine Kinase 2 Inhibitors for Treating Autoimmune and Inflammatory Diseases","authors":"Ram W. Sabnis*, ","doi":"10.1021/acsmedchemlett.4c00196","DOIUrl":"10.1021/acsmedchemlett.4c00196","url":null,"abstract":"<p >Provided herein are novel tyrosine kinase 2 inhibitors, pharmaceutical compositions, use of such compounds in treating autoimmune and inflammatory diseases, and processes for preparing such compounds.</p>","PeriodicalId":20,"journal":{"name":"ACS Medicinal Chemistry Letters","volume":null,"pages":null},"PeriodicalIF":4.2,"publicationDate":"2024-05-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140968167","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-05-15DOI: 10.1021/acsmedchemlett.4c00128
Thisara Jayawickrama Withanage, Mitra Lal, Ellen Wachtel and Guy Patchornik*,
The SARS-COV-2 virus is a deadly agent of inflammatory respiratory disease. Since 2020, studies have focused on developing new therapies based on galactose-rich IgA antibodies. Clinical surveys have also revealed that galactose-deficient IgA1 polymerizes in serum, producing IgA nephropathy, which is a common cause of kidney failure in young adults. Here we show that IgA1–IgA2 dimers are efficiently and economically purified in solution via conjugated nonionic surfactant micellar aggregates. Quantitative capture at pH 7 and extraction at pH 6.5 can avoid antibody exposure to acidic, potentially denaturing conditions. Brij-O20 aggregates lead to the highest process yields (88–91%) and purity (94%). Recovered IgA dimers preserve their native secondary structure and do not self-associate. Increasing the reaction volume has little impact on yield or purity. By introducing an efficient, inexpensive IgA purification protocol, we assist pharmaceutical firms and research laboratories in developing new IgA-based therapies as well as in increasing our understanding of IgA1 polymerization.
SARS-COV-2 病毒是一种致命的呼吸道炎症病原体。自 2020 年以来,研究的重点是开发基于富含半乳糖的 IgA 抗体的新疗法。临床调查还发现,半乳糖缺乏的 IgA1 会在血清中聚合,产生 IgA 肾病,这是青壮年肾衰竭的常见原因。在这里,我们展示了通过共轭非离子表面活性剂胶束聚集体在溶液中高效、经济地纯化 IgA1-IgA2 二聚体的方法。在 pH 值为 7 的条件下进行定量捕获,在 pH 值为 6.5 的条件下进行提取,可避免抗体暴露在酸性、可能变性的条件下。Brij-O20 聚合体的处理产量(88-91%)和纯度(94%)最高。回收的 IgA 二聚体保留了原生二级结构,不会发生自结合。增加反应体积对产量和纯度的影响很小。通过引入一种高效、廉价的 IgA 纯化方案,我们可以帮助制药公司和研究实验室开发基于 IgA 的新疗法,并加深我们对 IgA1 聚合作用的了解。
{"title":"Conjugated Nonionic Detergent Micelles: An Efficient Purification Platform for Dimeric Human Immunoglobulin A","authors":"Thisara Jayawickrama Withanage, Mitra Lal, Ellen Wachtel and Guy Patchornik*, ","doi":"10.1021/acsmedchemlett.4c00128","DOIUrl":"10.1021/acsmedchemlett.4c00128","url":null,"abstract":"<p >The SARS-COV-2 virus is a deadly agent of inflammatory respiratory disease. Since 2020, studies have focused on developing new therapies based on galactose-rich IgA antibodies. Clinical surveys have also revealed that galactose-deficient IgA1 polymerizes in serum, producing IgA nephropathy, which is a common cause of kidney failure in young adults. Here we show that IgA1–IgA2 dimers are efficiently and economically purified in solution via conjugated nonionic surfactant micellar aggregates. Quantitative capture at pH 7 and extraction at pH 6.5 can avoid antibody exposure to acidic, potentially denaturing conditions. Brij-O20 aggregates lead to the highest process yields (88–91%) and purity (94%). Recovered IgA dimers preserve their native secondary structure and do not self-associate. Increasing the reaction volume has little impact on yield or purity. By introducing an efficient, inexpensive IgA purification protocol, we assist pharmaceutical firms and research laboratories in developing new IgA-based therapies as well as in increasing our understanding of IgA1 polymerization.</p>","PeriodicalId":20,"journal":{"name":"ACS Medicinal Chemistry Letters","volume":null,"pages":null},"PeriodicalIF":4.2,"publicationDate":"2024-05-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140974608","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-05-14DOI: 10.1021/acsmedchemlett.4c00116
Zhen-Peng Yu, Xin Wang, Zhi-Qiang Yu, Hong Zhu, Jing-Xuan Miao, Hui Wang*, Hongwei Si* and Peng-Fei Dai*,
Many malignant tumors, including breast cancer, exhibit amplification and overexpression of cyclin-dependent kinase 4 and 6 (CDK4/6). Ribociclib, approved and used in clinical treatment, acts as a highly selective CDK4/6 inhibitor for ER+/HER2- breast cancer. By modifying ribociclib with the chelator DOTA, we designed and synthesized a novel CDK4/6-positive PET imaging agent, which was radiolabeled by 68Ga for radioactive tagging. The radiotracer demonstrates high radiochemical purity, excellent stability in vitro and in vivo, and favorable pharmacokinetic characteristics. Cell uptake experiments using MCF-7 cells indicate that an excess of ribociclib (RBB) can inhibit cellular uptake of 68Ga-DOTA-RBB. Imaging and biodistribution experiments in MCF-7 tumor-bearing nude mice show significant radioactive accumulation in the tumor. However, preadministration of excess ribociclib results in a substantial reduction in radioactive accumulation within the tumor. On the basis of our explorations, 68Ga-DOTA-RBB, as a targeted imaging agent for CDK4/6-positive tumors, holds significant potential application values.
{"title":"Synthesis and Preclinical Evaluation of Novel 68Ga-DOTA-RBB as Potential PET Radiotracer for Imaging CDK4/6 in Tumors","authors":"Zhen-Peng Yu, Xin Wang, Zhi-Qiang Yu, Hong Zhu, Jing-Xuan Miao, Hui Wang*, Hongwei Si* and Peng-Fei Dai*, ","doi":"10.1021/acsmedchemlett.4c00116","DOIUrl":"10.1021/acsmedchemlett.4c00116","url":null,"abstract":"<p >Many malignant tumors, including breast cancer, exhibit amplification and overexpression of cyclin-dependent kinase 4 and 6 (CDK4/6). Ribociclib, approved and used in clinical treatment, acts as a highly selective CDK4/6 inhibitor for ER+/HER2- breast cancer. By modifying ribociclib with the chelator DOTA, we designed and synthesized a novel CDK4/6-positive PET imaging agent, which was radiolabeled by <sup>68</sup>Ga for radioactive tagging. The radiotracer demonstrates high radiochemical purity, excellent stability <i>in vitro</i> and <i>in vivo</i>, and favorable pharmacokinetic characteristics. Cell uptake experiments using MCF-7 cells indicate that an excess of ribociclib (RBB) can inhibit cellular uptake of <sup>68</sup>Ga-DOTA-RBB. Imaging and biodistribution experiments in MCF-7 tumor-bearing nude mice show significant radioactive accumulation in the tumor. However, preadministration of excess ribociclib results in a substantial reduction in radioactive accumulation within the tumor. On the basis of our explorations, <sup>68</sup>Ga-DOTA-RBB, as a targeted imaging agent for CDK4/6-positive tumors, holds significant potential application values.</p>","PeriodicalId":20,"journal":{"name":"ACS Medicinal Chemistry Letters","volume":null,"pages":null},"PeriodicalIF":4.2,"publicationDate":"2024-05-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140981600","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}