MedChemComm最新文献_第3页

Design, synthesis, molecular modelling investigation and biological studies of novel human carbonic anhydrase inhibitors based on coumalic acid† 基于香苹果酸的新型人碳酸酐酶抑制剂的设计、合成、分子模拟研究和生物学研究。

IF 3.597

MedChemComm Pub Date : 2025-05-30 DOI: 10.1039/D5MD00208G

Virginia Pontecorvi, Andrea Angeli, Luigi Cutarella, Mattia Mori, Daniela Secci, Michele Coluccia, Simone Carradori, Anna Troiani, Federico Pepi, Chiara Salvitti, Alessia Di Noi, Mattia Spano, Francesca Arrighi, Elena De Falco, Antonella Bordin, Emanuela Berrino, Arianna Granese, Paola Chimenti, Paolo Guglielmi and Claudiu T. Supuran

{"title":"Design, synthesis, molecular modelling investigation and biological studies of novel human carbonic anhydrase inhibitors based on coumalic acid†","authors":"Virginia Pontecorvi, Andrea Angeli, Luigi Cutarella, Mattia Mori, Daniela Secci, Michele Coluccia, Simone Carradori, Anna Troiani, Federico Pepi, Chiara Salvitti, Alessia Di Noi, Mattia Spano, Francesca Arrighi, Elena De Falco, Antonella Bordin, Emanuela Berrino, Arianna Granese, Paola Chimenti, Paolo Guglielmi and Claudiu T. Supuran","doi":"10.1039/D5MD00208G","DOIUrl":"10.1039/D5MD00208G","url":null,"abstract":"The present study provides the design, synthesis, molecular modelling investigation and biological evaluation of a series of coumalic acid-based selective inhibitors of hCA IX and XII. Based on the previously obtained results with carboxamide analogues of coumalic acid, here we explored some modifications of the original scaffold with the aim to expand our knowledge about these compounds and to promote structure–activity relationship (SAR) studies. Structural modifications as lactone-to-lactam conversion, repositioning of the carboxylic acid moiety, and the introduction of ester or amidic linkers, as well as triazole-based elongation via click chemistry have been performed. The synthesised compounds were tested for their inhibitory activities against hCA I, II, IX, and XII showing the lactone moiety to be crucial for inhibitory potency. Particularly, ester derivatives demonstrated selectivity for hCA IX and XII, with certain compounds exhibiting micromolar affinities. Notably, compound 8, featuring a bromine substitution, displayed the highest selectivity and potency against hCA IX and XII. Molecular docking studies further elucidated the binding mechanisms, revealing that the lactone ring hydrolysis plays a significant role in the inhibition process. These results offer valuable insights into the structure–activity relationships (SAR) of coumalic acid analogues and support their further biological investigation for cancer therapy by targeting hCA IX and XII.","PeriodicalId":88,"journal":{"name":"MedChemComm","volume":" 8","pages":" 3603-3621"},"PeriodicalIF":3.597,"publicationDate":"2025-05-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12124219/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144199881","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Identification of alkynyl nicotinamide HSN748 as a RET solvent-front mutant inhibitor with intracranial efficacy† 炔基烟酰胺HSN748作为RET溶剂前突变抑制剂的鉴定。

IF 3.597

MedChemComm Pub Date : 2025-05-28 DOI: 10.1039/D5MD00245A

Ujjwol Khatri, Neetu Dayal, Kofi B. Owusu, Mandeep Kaur Hunjan, Shriya Pandey, Haley Anne Harper, Carli McMahan, Bennett D. Elzey, Tao Shen, Xueqing Hu, Kurt W. Evans, Ahmed El-Sheikh, Seong jun Jo, Frederick W. Holtsberg, M. Javad Aman, Funda Meric-Bernstam, Sukyung Woo, Herman O. Sintim and Jie Wu

{"title":"Identification of alkynyl nicotinamide HSN748 as a RET solvent-front mutant inhibitor with intracranial efficacy†","authors":"Ujjwol Khatri, Neetu Dayal, Kofi B. Owusu, Mandeep Kaur Hunjan, Shriya Pandey, Haley Anne Harper, Carli McMahan, Bennett D. Elzey, Tao Shen, Xueqing Hu, Kurt W. Evans, Ahmed El-Sheikh, Seong jun Jo, Frederick W. Holtsberg, M. Javad Aman, Funda Meric-Bernstam, Sukyung Woo, Herman O. Sintim and Jie Wu","doi":"10.1039/D5MD00245A","DOIUrl":"10.1039/D5MD00245A","url":null,"abstract":"RET solvent-front G810C/R/S mutations confer resistance to the currently approved RET protein tyrosine kinase inhibitors (TKIs) selpercatinib and pralsetinib. Moreover, RET fusion-positive lung adenocarcinoma frequently metastasizes to the brain. To address these challenges, it is imperative to develop a RET TKI that is effective against solvent-front mutations and exhibits intracranial activity. We synthesized alkynyl nicotinamide-based RET TKIs and tested their efficacy in cell cultures in inhibiting selpercatinib/pralsetinib-resistant RET solvent-front mutants G810C/R/S found in cancer patients, and in BaF3/KIF5B-RET(G810C) cell-derived subcutaneous and intracranial tumors in vivo. We also evaluated alkynyl nicotinamide RET TKIs in KIF5B-RET-induced lung tumors in immune competent transgenic mice, and in CCDC6-RET fusion-positive thyroid patient-derived xenograft PDX.003.047 tumors. In vivo pharmacokinetics (PK) studies were conducted to determine drug concentrations in plasma and brain. HSN748, HSND19, and HSND14 demonstrated potent inhibition of RET G810C/R/S mutants, with low nanomolar IC50 values. HSN748 induced regression of subcutaneous B/KR(G810C) tumors without causing body weight loss. Both HSN748 and HSND19 significantly reduced KIF5B-RET-driven lung tumors in transgenic mice, and inhibited growth of CCDC6-RET-positive PDX tumors. Among three compounds (HSN748, HSND19, and HSN608) evaluated for B/KR(G810C) brain tumors, HSN748 exhibited significant intracranial tumor inhibition. PK analysis indicated that HSN748 has a brain/plasma partition coefficient (Kp) of 0.4, demonstrating its capability to penetrate the central nervous system (CNS).","PeriodicalId":88,"journal":{"name":"MedChemComm","volume":" 8","pages":" 3541-3550"},"PeriodicalIF":3.597,"publicationDate":"2025-05-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12147034/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144267231","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Design, synthesis, and biological evaluation of substituted oxopyridine derivatives as selective FXIa inhibitors† 取代氧吡啶衍生物作为选择性FXIa抑制剂的设计、合成和生物学评价。

IF 3.597

MedChemComm Pub Date : 2025-05-28 DOI: 10.1039/D4MD01013B

Yanshi Wang, Sida Yan, Jianglin Yuan, Xiaoyan Meng, Peng Liu, Shijun Zhang, Fancui Meng, Wei Liu, Shuhao Zhang, Changjiang Huang and Qunchao Wei

引用次数: 0

Design, synthesis, molecular modeling, and antiproliferative evaluation of new 2-oxoindolin-3-ylidene thiazole derivatives† 新的2-氧吲哚-3-酰基噻唑衍生物的设计、合成、分子模拟和抗增殖性评价。

IF 3.597

MedChemComm Pub Date : 2025-05-28 DOI: 10.1039/D5MD00332F

Aalaa F. El-Mokadem, Mohammed K. Abd El-Gaber, Pak Hei Chung, Siang-Boon Koh, Hoda Y. Hassan and Adel F. Youssef

{"title":"Design, synthesis, molecular modeling, and antiproliferative evaluation of new 2-oxoindolin-3-ylidene thiazole derivatives†","authors":"Aalaa F. El-Mokadem, Mohammed K. Abd El-Gaber, Pak Hei Chung, Siang-Boon Koh, Hoda Y. Hassan and Adel F. Youssef","doi":"10.1039/D5MD00332F","DOIUrl":"10.1039/D5MD00332F","url":null,"abstract":"A series of novel 2-oxoindolin-3-ylidene thiazole derivatives were designed and synthesized, inspired by the pharmacophoric features of the VEGFR-2 inhibitor sunitinib. These compounds were evaluated for antiproliferative activity against a panel of sixty cancer cell lines at the US National Cancer Institute, identifying derivatives 4b, 4c, 4d, 4l, and 6c as the most potent, with mean growth inhibition percentages of 118.86%, 135.32%, 148.27%, 126.16%, and 78.46%, respectively. Further cytotoxicity assessments against the HepG2 cell line revealed IC50 values ranging from 3.13 to 30.54 μM. These compounds also demonstrated strong VEGFR-2 inhibition, with IC50 values of 0.113, 0.047, 1.549, 0.995, and 0.089 μM, respectively, compared to sunitinib's IC50 of 0.167 μM. Selectivity index analysis indicated high selectivity for HepG2 cells over THLE-2 normal cells (1.80–10.26), suggesting favourable safety profiles compared to sunitinib (1.15). Notably, compound 4c induced G0/G1 phase cell cycle arrest, promoted apoptosis, upregulated caspase-3 and -9 expression, and delayed wound closure by 60.74%. Molecular docking studies confirmed strong binding interactions within the VEGFR-2 active site, while in silico ADME and DFT analyses supported favourable pharmacokinetic properties and reactivity. These findings position compound 4c as a promising lead for the development of anticancer agents.","PeriodicalId":88,"journal":{"name":"MedChemComm","volume":" 8","pages":" 3645-3670"},"PeriodicalIF":3.597,"publicationDate":"2025-05-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144216798","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Novel benzimidazole hybrids: design, synthesis, mechanistic studies, antifungal potential and molecular dynamics† 新型苯并咪唑杂交种：设计、合成、机理研究、抗真菌潜能和分子动力学。

IF 3.597

MedChemComm Pub Date : 2025-05-27 DOI: 10.1039/D5MD00122F

Ahmed A. Ibrahim, Eman G. Said, Asmaa M. AboulMagd, Noha H. Amin and Hamdy M. Abdel-Rahman

{"title":"Novel benzimidazole hybrids: design, synthesis, mechanistic studies, antifungal potential and molecular dynamics†","authors":"Ahmed A. Ibrahim, Eman G. Said, Asmaa M. AboulMagd, Noha H. Amin and Hamdy M. Abdel-Rahman","doi":"10.1039/D5MD00122F","DOIUrl":"10.1039/D5MD00122F","url":null,"abstract":"In this study, two series of benzimidazole hybrids were developed and designed using different strategies. The target compounds were designed through straight chemistry pathways and were screened as possible antimicrobial agents. Twenty new compounds were synthesized, among which compounds 11 and 12 displayed excellent activity against Candida albicans and Cryptococcus neoformans with growth inhibition percentage ranging from 86.42% to 100%. For gaining better insights into the mechanistic ability of the active candidates 11 and 12, their inhibitory activity against lanosterol 14α-demethylase was studied. Results showed IC50 values of 5.6 and 7.1 μM for 11 and 12, respectively, which were comparable to the reference value of fluconazole (2.3 μM), indicating low drug interaction possibilities. Notably, compound 11 displayed excellent inhibition of biofilm metabolic activity. In addition, their synergistic activity against C. neoformans displayed a 2-fold increase compared with fluconazole. Furthermore, it exhibited sustained antifungal activity with time clearance of over 24 h, which was better than the time clearance of fluconazole (6 h). Moreover, compounds 11 and 12 displayed considerable safety profiles, with no cytotoxicity reported against human embryonic kidney cells or hemolysis of red blood cells. Molecular dynamics simulation (MDS) experiments over 100 ns of compound 11 showed its ability to interact with the HEM binding site as the co-crystallized ligand (fluconazole). Finally, in silico ADMET studies predicted its significant oral bioavailability as antifungal candidates.","PeriodicalId":88,"journal":{"name":"MedChemComm","volume":" 7","pages":" 3291-3311"},"PeriodicalIF":3.597,"publicationDate":"2025-05-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144174784","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

The relationship between cancer risk and cystic fibrosis: the role of CFTR in cell growth and cancer development 癌症风险与囊性纤维化之间的关系：CFTR在细胞生长和癌症发展中的作用。

IF 3.597

MedChemComm Pub Date : 2025-05-27 DOI: 10.1039/D5MD00203F

Radek Indra and Věra Černá

{"title":"The relationship between cancer risk and cystic fibrosis: the role of CFTR in cell growth and cancer development","authors":"Radek Indra and Věra Černá","doi":"10.1039/D5MD00203F","DOIUrl":"10.1039/D5MD00203F","url":null,"abstract":"Cystic fibrosis (CF) is a life-limiting genetic disease that affects multiple organ systems. It is caused by a mutation of the cystic fibrosis transmembrane conductance regulator (CFTR) gene, which results in the absence or damage of a relevant protein. If left untreated, it causes death in early childhood. The advent of more efficacious treatments has resulted in a notable increase in the life expectancy of CF patients. This has, in turn, led to an elevated risk of developing specific types of cancer. This review commences with an examination of CF from the standpoint of its etiology and therapeutic modalities. Subsequently, it presents a list of epidemiological studies that suggest an altered predisposition to certain cancers. A heightened risk is well documented, particularly in relation to the gastrointestinal tract. The following section addresses the role of CFTR in view of its potential involvement in the progression of various types of cancer. Several studies have indicated that the levels of the CFTR protein are reduced in many tumors and that this reduction is associated with the progression of the tumors. These decreased expressions are known to occur in the gastrointestinal tract, lungs, bladder, and/or prostate cancer. Conversely, ovarian, stomach, and cervical cancer are connected with its higher expression. The final section of the review focuses on the molecular mechanism of action of the CFTR protein in signaling pathways that affect cell proliferation and the process of carcinogenesis. This section attempts to explain the increased predisposition to cancer observed in patients with CF.","PeriodicalId":88,"journal":{"name":"MedChemComm","volume":" 8","pages":" 3416-3428"},"PeriodicalIF":3.597,"publicationDate":"2025-05-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12107394/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144174789","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Five years of research on 2,4-thiazolidinediones as anticancer agents: medicinal chemistry insights (2020–2024) 2,4-噻唑烷二酮类抗癌药物的五年研究：药物化学见解（2020-2024）

IF 3.597

MedChemComm Pub Date : 2025-05-27 DOI: 10.1039/D5MD00344J

Neeru Malik and Rajesh Kumar Singh

{"title":"Five years of research on 2,4-thiazolidinediones as anticancer agents: medicinal chemistry insights (2020–2024)","authors":"Neeru Malik and Rajesh Kumar Singh","doi":"10.1039/D5MD00344J","DOIUrl":"10.1039/D5MD00344J","url":null,"abstract":"2,4-Thiazolidinediones (2,4-TZDs) are a class of heterocyclic compounds traditionally recognized for their antidiabetic activity, particularly as peroxisome proliferator-activated receptor gamma (PPARγ) agonists. However, in recent years, they have emerged as promising anticancer scaffolds due to their ability to influence key molecular pathways involved in tumorigenesis, including cell proliferation, apoptosis, angiogenesis, and metastasis. The structural flexibility of the 2,4-TZD core—especially at the C-5 position—makes it highly amenable to derivatization, offering opportunities to fine-tune bioactivity and selectivity. This review presents a focused evaluation of 2,4-TZD derivatives reported between 2020 and 2024, emphasizing structure–activity relationship (SAR) studies and their implications for anticancer drug design. We discuss how various substituent modifications influence cytotoxic potency and target selectivity. In addition, we explore the molecular mechanisms underlying the anticancer activity of selected 2,4-TZD derivatives, along with an overview of their pharmacological relevance. This compilation aims to serve as a valuable resource for medicinal chemists and drug discovery researchers working on next-generation 2,4-TZDs as targeted anticancer therapeutics.","PeriodicalId":88,"journal":{"name":"MedChemComm","volume":" 8","pages":" 3344-3361"},"PeriodicalIF":3.597,"publicationDate":"2025-05-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144317824","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Synthetic chemistry enabling the discovery and development of a series of pyrazoles as HPK1 inhibitors† 合成化学使一系列吡唑类HPK1抑制剂得以发现和开发。

IF 3.597

MedChemComm Pub Date : 2025-05-27 DOI: 10.1039/D5MD00309A

Anthony J. Metrano, Lucas A. Morrill, Gayathri Bommakanti, Robert Casella, Steve Cook, Randolph A. Escobar, Kathryn A. Giblin, Eric Gosselin, Tyler Grebe, Niresh Hariparsad, Rachel Howells, Gillian M. Lamont, Deanna A. Mele, Alexander Pflug, Theresa A. Proia, Hadi Rezaei, Magdalena Richter, Ryan Richards, Maryann San Martin, Marianne Schimpl, Alwin G. Schuller, Li Sha, James E. Sheppeck, Kun Song, Haoran Tang, David J. Wagner, Jianyan Wang, Allan Wu, Dedong Wu, Ye Wu, Kevin Xu, Minwei Ye, Jason D. Shields and Neil P. Grimster

{"title":"Synthetic chemistry enabling the discovery and development of a series of pyrazoles as HPK1 inhibitors†","authors":"Anthony J. Metrano, Lucas A. Morrill, Gayathri Bommakanti, Robert Casella, Steve Cook, Randolph A. Escobar, Kathryn A. Giblin, Eric Gosselin, Tyler Grebe, Niresh Hariparsad, Rachel Howells, Gillian M. Lamont, Deanna A. Mele, Alexander Pflug, Theresa A. Proia, Hadi Rezaei, Magdalena Richter, Ryan Richards, Maryann San Martin, Marianne Schimpl, Alwin G. Schuller, Li Sha, James E. Sheppeck, Kun Song, Haoran Tang, David J. Wagner, Jianyan Wang, Allan Wu, Dedong Wu, Ye Wu, Kevin Xu, Minwei Ye, Jason D. Shields and Neil P. Grimster","doi":"10.1039/D5MD00309A","DOIUrl":"10.1039/D5MD00309A","url":null,"abstract":"Hematopoietic progenitor kinase 1 (HPK1) is a negative regulator of T-cell signaling. Inhibition of HPK1 with small molecules has been shown to reinvigorate the immune system toward fighting tumours in preclinical models, thus it holds promise as a therapeutic strategy in cancer immunotherapy. Herein we report a series of pyrazine carboxamide pyrazoles as selective inhibitors of HPK1. Key to our approach was the development of late-stage functionalisation chemistry which allowed for rapid SAR generation. Through these efforts, we discovered difluoroethyl pyrazole 16a, an in vivo tool which elicited the desired pharmacodynamic response in mice. Further, we describe the optimization of synthetic chemistry which could support preclinical studies of a member of this series of substituted pyrazoles.","PeriodicalId":88,"journal":{"name":"MedChemComm","volume":" 8","pages":" 3522-3529"},"PeriodicalIF":3.597,"publicationDate":"2025-05-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144302813","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Evolution of structure-guided drug design strategies targeting mutations in codon 12 of KRAS 靶向KRAS密码子12突变的结构导向药物设计策略的进化

IF 3.597

MedChemComm Pub Date : 2025-05-26 DOI: 10.1039/D5MD00169B

Sadaf Dorandish, Komal Bhayekar, Anuradha Singh, Narva Deshwar Kushwaha, Evan Malin, Sara Serafimovski, Jeremy M. Kelm, Navnath S. Gavande and Naga Rajiv Lakkaniga

{"title":"Evolution of structure-guided drug design strategies targeting mutations in codon 12 of KRAS","authors":"Sadaf Dorandish, Komal Bhayekar, Anuradha Singh, Narva Deshwar Kushwaha, Evan Malin, Sara Serafimovski, Jeremy M. Kelm, Navnath S. Gavande and Naga Rajiv Lakkaniga","doi":"10.1039/D5MD00169B","DOIUrl":"10.1039/D5MD00169B","url":null,"abstract":"KRAS mutations at codon 12 are among the most frequent driver mutations oncogenic alterations in various cancers and associated with aggressive disease and poor clinical outcomes. Historically, KRAS had been a very difficult target due to its strong binding to GDP/GTP and the lack of available druggable binding pockets. Considerable advances have been achieved in generating direct small-molecule inhibitors selectively targeting KRAS G12 mutations. This review discusses the development of approaches to design inhibitors that bind directly to KRAS, starting from the pioneering work of the Shokat group. This review details significant milestones of KRAS-targeted drug discovery and the current impediments in this field. The identification of covalent inhibitors of the KRAS G12C and more recently a direct inhibitor of K-Ras G12C in a GTP-bound state exemplifies the promise of this approach. Structure-guided drug design improved the basis for understanding the mutations in KRAS, notably at codon 12, and the idea has potential for gene therapy. Focusing exclusively on direct and indirect KRAS inhibitors, this review highlights the evolving strategies transforming KRAS from an elusive target to a tractable therapeutic opportunity, offering new hope for patients with KRAS-driven cancers.","PeriodicalId":88,"journal":{"name":"MedChemComm","volume":" 8","pages":" 3429-3455"},"PeriodicalIF":3.597,"publicationDate":"2025-05-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144235036","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Discovery of PZ671, a highly potent and in vivo active CRBN-recruiting Bcl-xL degrader† PZ671，一种高效的体内活性crbn招募Bcl-xL降降剂的发现。

IF 3.597

MedChemComm Pub Date : 2025-05-23 DOI: 10.1039/D5MD00119F

Peiyi Zhang, Dinesh Thummuri, Wanyi Hu, Sajid Khan, Yonghan He, Xuan Zhang, Pratik Pal, Dongwen Lv, Daohong Zhou and Guangrong Zheng

{"title":"Discovery of PZ671, a highly potent and in vivo active CRBN-recruiting Bcl-xL degrader†","authors":"Peiyi Zhang, Dinesh Thummuri, Wanyi Hu, Sajid Khan, Yonghan He, Xuan Zhang, Pratik Pal, Dongwen Lv, Daohong Zhou and Guangrong Zheng","doi":"10.1039/D5MD00119F","DOIUrl":"10.1039/D5MD00119F","url":null,"abstract":"The conversion of conventional inhibitors of Bcl-xL, a key anti-apoptotic protein, to PROTAC degraders has shown significant promise, particularly in mitigating the on-target thrombocytopenia associated with Bcl-xL inhibition but improving their potency. Previously, we reported XZ739, a CRBN-recruiting Bcl-xL PROTAC that was 20-fold more potent than its parent inhibitor ABT-263 against Bcl-xL-dependent MOLT-4 cells while reducing toxicity to human platelets. Building on XZ739, we here report the discovery of PZ671, a more potent Bcl-xL degrader with ∼10-fold improved cellular activity against MOLT-4 cells (IC50 = 1.3 nM) and ∼6-fold enhanced degradation potency against Bcl-xL (DC50 = 0.9 nM) as well as superior potency across multiple SCLC cell lines compared to XZ739. In vivo studies revealed that PZ671 could effectively inhibit MOLT-4 xenograft growth in mice but caused only a moderate and transient reduction in platelet counts following its administration. Our findings highlight the potential of CRBN-recruiting Bcl-xL degraders as promising anticancer agents with improved efficacy and manageable platelet toxicity.","PeriodicalId":88,"journal":{"name":"MedChemComm","volume":" 8","pages":" 3495-3506"},"PeriodicalIF":3.597,"publicationDate":"2025-05-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12155403/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144286463","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0