Journal of Medicinal Chemistry最新文献_第8页

Rational Design of Near-Infrared Difluoroboron Cyanine Photosensitizers for Lipid Droplet-Targeting Imaging and Tumor Therapy 用于脂滴靶向成像和肿瘤治疗的近红外二氟硼氰光敏剂的合理设计

IF 7.3 1区医学

Journal of Medicinal Chemistry Pub Date : 2026-10-12 DOI: 10.1021/acs.jmedchem.6c01845

Li Chen,Yutong Wang,Jun Yang,Qian Li,Shuming Chen,Yong Wang,Wuyu Mao,Jifa Zhang

{"title":"Rational Design of Near-Infrared Difluoroboron Cyanine Photosensitizers for Lipid Droplet-Targeting Imaging and Tumor Therapy","authors":"Li Chen,Yutong Wang,Jun Yang,Qian Li,Shuming Chen,Yong Wang,Wuyu Mao,Jifa Zhang","doi":"10.1021/acs.jmedchem.6c01845","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.6c01845","url":null,"abstract":"Specifically disrupting lipid droplets (LDs) is an effective strategy for ablating tumor cells through photodynamic therapy (PDT). However, most reported LD probes possess short excitation/emission wavelengths, limiting tissue penetration, and LD-targeted theranostic probes remain underdeveloped. In this work, we first developed a family of near-infrared (NIR) charge-neutral and lipid droplet-targeting cyanine photosensitizers by systematically introducing heavy atoms (Br/I) at different sites of electrically neutral BF2-bridged cyanine (BCy5). These BCy photosensitizers retain the characteristic near-infrared absorption (>650 nm) and high molar extinction coefficients of classical cyanine dyes while exhibiting good singlet oxygen quantum yields. Notably, BCy5-Br1−BCy5-Br3 nanoparticles with high LD specificity exhibit significant PDT efficacy at submicromolar concentrations and, by inducing oxidative stress and lipid peroxidation (LPO) accumulation, concurrently trigger apoptosis and ferroptosis, effectively suppressing melanoma growth in vivo. This work provides vital insights into design principles and transformation of LD-targeting NIR cyanine photosensitizers for cancer PDT.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"10 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2026-10-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149152135","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}

引用次数: 0

Development of DCL1191 as a Potent, Selective and Orally Bioavailable Inhibitor for Autophagy-Associated Transcription Factor EB (TFEB) DCL1191作为自噬相关转录因子EB （TFEB）有效、选择性和可口服抑制剂的研究进展

IF 7.3 1区医学

Journal of Medicinal Chemistry Pub Date : 2026-10-12 DOI: 10.1021/acs.jmedchem.6c01755

Changle Du,Yaping Rong,Zilu Wang,Tongtong Wang,Yuqi Lin,Yuhan Luo,Yuhan Su,Pengfei Fang,Biao Yu,Zhen Wang,Jing Wang,Ke Ding

{"title":"Development of DCL1191 as a Potent, Selective and Orally Bioavailable Inhibitor for Autophagy-Associated Transcription Factor EB (TFEB)","authors":"Changle Du,Yaping Rong,Zilu Wang,Tongtong Wang,Yuqi Lin,Yuhan Luo,Yuhan Su,Pengfei Fang,Biao Yu,Zhen Wang,Jing Wang,Ke Ding","doi":"10.1021/acs.jmedchem.6c01755","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.6c01755","url":null,"abstract":"Transcription factor EB (TFEB) is a promising target for autophagy regulation and cancer therapy, yet it has long been regarded as an undruggable protein. Starting from eltrombopag, an FDA-approved agent that exhibits both thrombopoietin receptor (Tpo-R) agonistic activity and TFEB inhibitory potency, we performed systematic structure−activity relationship optimization and identified DCL1191 as a potent, selective, and orally bioavailable TFEB inhibitor. DCL1191 binds TFEB with a Kd of 80.5 nM and disrupts the TFEB-DNA interaction with an IC50 of 60.5 nM. Computational modeling combined with site-directed mutagenesis elucidated its precise binding mode. DCL1191 exhibits diminished activity toward Tpo-R and MITF. Mechanistically, DCL1191 effectively represses the transcription of TFEB target genes and blocks intracellular autophagic flux. In autophagy-hyperactivated U87 glioblastoma cells, DCL1191 substantially sensitizes tumor cells to temozolomide chemotherapy. Pharmacokinetic evaluation in rats further demonstrated that DCL1191 possesses an i.v. half-life of 16.33 h and satisfactory oral bioavailability of 18.77%.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"9 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2026-10-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149152136","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}

引用次数: 0

Evaluation of 68Ga Labeling Strategies and Thermostability of HER2-Targeted Nanobody NB46 her2靶向纳米体NB46的68Ga标记策略及热稳定性评价

IF 7.3 1区医学

Journal of Medicinal Chemistry Pub Date : 2026-10-10 DOI: 10.1021/acs.jmedchem.6c02664

Lingzhou Zhao,Liyan Bai,Jiamin Zhu,Li Sun,Xinyu Liu,Xin Lu,Jianping Zhang,Xiaoping Xu,Shaoli Song

{"title":"Evaluation of 68Ga Labeling Strategies and Thermostability of HER2-Targeted Nanobody NB46","authors":"Lingzhou Zhao,Liyan Bai,Jiamin Zhu,Li Sun,Xinyu Liu,Xin Lu,Jianping Zhang,Xiaoping Xu,Shaoli Song","doi":"10.1021/acs.jmedchem.6c02664","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.6c02664","url":null,"abstract":"Abstract The HER2-targeted nanobody NB46 was evaluated for labeling strategy flexibility and thermostability. Random and site-specific 68Ga labeling strategies were compared. Both conjugates exhibited high HER2 affinity, comparable to unmodified NB46. Cellular uptake, pharmacokinetics, micro-PET/CT imaging, and biodistribution in HER2-positive and HER2-negative tumor-bearing mice revealed no significant differences between the two strategies. NB46 retained HER2 affinity at temperatures up to 90 °C, demonstrating exceptional thermostability. Both conjugates achieved &gt;95% radiochemical yields at all tested temperatures. Micro-PET/CT imaging showed sustained high tumor uptake with renal clearance as the primary elimination pathway. Blocking studies confirmed that NB46 and trastuzumab competitively bind to HER2. Elevated labeling temperatures did not compromise tumor targeting but resulted in a mild increase in renal uptake, notably for the random conjugate at 90 °C. These findings suggest that random labeling may represent a simpler, equally effective alternative for 68Ga-NB46 preparation, and confirm the excellent thermostability of this nanobody scaffold.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"29 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2026-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149151429","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}

引用次数: 0

Design, Synthesis and Evaluation Donepezil-Based Dual BuChE/FAAH Inhibitors for Alzheimer’s Disease Therapy 多奈哌齐双BuChE/FAAH抑制剂治疗阿尔茨海默病的设计、合成和评价

IF 7.3 1区医学

Journal of Medicinal Chemistry Pub Date : 2026-10-10 DOI: 10.1021/acs.jmedchem.6c01848

Xiaodan Liu,Yinxin Wu,Yulu Ding,Shilin Hu,Hui Hou,Yicheng Zong,Ziwen Zhang,Wenjian Tang

引用次数: 0

A Selective Bis-Catecholate Siderophore-Ampicillin Conjugate Expands Activity against Multidrug-Resistant Pseudomonas aeruginosa 选择性双儿茶酚酸铁载体氨苄西林偶联物增强抗多重耐药铜绿假单胞菌活性

IF 7.3 1区医学

Journal of Medicinal Chemistry Pub Date : 2026-10-10 DOI: 10.1021/acs.jmedchem.6c02268

Liang Zhong,Chenyuan Wang,Suyu Wang,Huimiao Zhang,Richard Yi-Tsun Kao,Patrick Henry Toy,Pak-Leung Ho,Hongyan Li,Hongzhe Sun

{"title":"A Selective Bis-Catecholate Siderophore-Ampicillin Conjugate Expands Activity against Multidrug-Resistant Pseudomonas aeruginosa","authors":"Liang Zhong,Chenyuan Wang,Suyu Wang,Huimiao Zhang,Richard Yi-Tsun Kao,Patrick Henry Toy,Pak-Leung Ho,Hongyan Li,Hongzhe Sun","doi":"10.1021/acs.jmedchem.6c02268","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.6c02268","url":null,"abstract":"Abstract Antimicrobial resistance is a global public health crisis, with multidrug-resistant P. aeruginosa among the most critical threats. The high cost and slow pace of novel antibiotic development, coupled with rapid resistance evolution, demand innovative strategies. Here, we present a Trojan horse approach using siderophore-antibiotic conjugates (SACs) to hijack bacterial iron uptake systems and deliver β-lactam payloads across the Gram-negative outer membrane. We designed a series of ampicillin conjugates with mono-catecholate, bis-catecholate, and catecholate-hydroxamate siderophores. These conjugates demonstrate potent antimicrobial activity. Notably, the lead compound, BC-2-Amp, shows broad-spectrum and highly selective activity against a panel of 105 clinical isolates of P. aeruginosa. Mechanistic studies demonstrated that BC-2-Amp utilizes PiuA as a critical receptor for targeted delivery. Complementary in vivo experiments further confirmed its promising therapeutic efficacy. Collectively, these findings establish SACs as a potent strategy for broadening the spectrum of β-lactam antibiotics and provide a robust platform for high-potency drug delivery.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"10 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2026-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149151428","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}

引用次数: 0

Maleimide−Thiol Conjugation Enables the Optimization of 68Ga-Labeled CAIX Targeting PET Probes 马来酰亚胺-巯基偶联使68ga标记的CAIX靶向PET探针的优化

IF 7.3 1区医学

Journal of Medicinal Chemistry Pub Date : 2026-10-10 DOI: 10.1021/acs.jmedchem.6c01607

Yonghao Li,Aiyan Ji,Boyu Tan,Xiaonan Wei,Yibin Wu,Renli Luo,Yeshan Qin,Luming Sun,Nianting Ju,Jiamin Zhu,Chaoquan Lai,Hongyue Lou,Chunrong Qu,Zhen Cheng

{"title":"Maleimide−Thiol Conjugation Enables the Optimization of 68Ga-Labeled CAIX Targeting PET Probes","authors":"Yonghao Li,Aiyan Ji,Boyu Tan,Xiaonan Wei,Yibin Wu,Renli Luo,Yeshan Qin,Luming Sun,Nianting Ju,Jiamin Zhu,Chaoquan Lai,Hongyue Lou,Chunrong Qu,Zhen Cheng","doi":"10.1021/acs.jmedchem.6c01607","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.6c01607","url":null,"abstract":"Abstract Carbonic anhydrase IX (CAIX) is a well-established biomarker of tumor hypoxia and an attractive target for molecular imaging. Despite the development of small-molecule CAIX-targeting positron emission tomography (PET) probes, most exhibit high normal-organ uptake and suboptimal tumor-to-background contrast. Moreover, their application in hypoxic tumors remains insufficiently explored. Herein, we reported four 68Ga-labeled CAIX-targeting probes based on the acetazolamide (AAZ) scaffold, employing distinct conjugation strategies, including amide coupling and maleimide−thiol ligation. All probes demonstrated detectable tumor uptake in vivo. Among them, [68Ga]Ga-SMIC-2607 displayed the highest tumor uptake (14.67 ± 3.06 %ID/g) and tumor-to-kidney ratio (1.69 ± 0.41) at 1 h in subcutaneous OS-RC-2-bearing mice, along with high tumor uptake in HT-29-bearing mice (2.98 ± 0.28 %ID/g at 1 h). Overall, [68Ga]Ga-SMIC-2607 demonstrates favorable imaging characteristics, with high tumor uptake and high tumor-to-normal organ ratios, representing a promising candidate for imaging CAIX-overexpressing tumors and supporting clinical translation.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"9 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2026-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149151430","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}

引用次数: 0

Enzyme−Targeted Therapeutics for Neurological Disorders 酶靶向治疗神经系统疾病

IF 7.3 1区医学

Journal of Medicinal Chemistry Pub Date : 2026-10-10 DOI: 10.1021/acs.jmedchem.6c01274

Leonardo Massignan,Lokesh Kanduru,Sara Ziadat,David Uehling,Donald F. Weaver,Mark A. Reed

{"title":"Enzyme−Targeted Therapeutics for Neurological Disorders","authors":"Leonardo Massignan,Lokesh Kanduru,Sara Ziadat,David Uehling,Donald F. Weaver,Mark A. Reed","doi":"10.1021/acs.jmedchem.6c01274","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.6c01274","url":null,"abstract":"Abstract Neurological disorders represent one of the leading causes of disability and mortality worldwide, and their prevalence is expected to increase substantially with population aging. Despite major advances in neuroscience, effective disease-modifying therapies remain unavailable for most chronic disorders of the central nervous system (CNS), highlighting the need for novel therapeutic strategies. Enzymes are attractive drug targets because they regulate fundamental processes including neurotransmission, signal transduction, energy metabolism, protein homeostasis, epigenetic regulation, lipid metabolism, and cellular detoxification. This review summarizes the major classes of druggable CNS enzymes, discuss clinically approved drugs and emerging investigational agents, and evaluate therapeutic opportunities across neurodegenerative, neurodevelopmental, neuropsychiatric, cerebrovascular, and neuro-oncologic diseases. Key challenges including blood−brain barrier penetration, target selectivity, off-target pharmacology, and clinical translation are also examined. By integrating diverse enzyme-targeting modalities across multiple neurological disorders, this review highlights both the progress achieved to date and the substantial opportunities that remain for future CNS drug discovery.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"170 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2026-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149151433","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}

引用次数: 0

A Peripheral Sulfonium Moiety Engineering Strategy to Enhance AIEgen-Based Antitumor Photodynamic Therapy 外周磺胺片段工程策略增强基于aiegen的抗肿瘤光动力治疗

IF 7.3 1区医学

Journal of Medicinal Chemistry Pub Date : 2026-10-10 DOI: 10.1021/acs.jmedchem.6c01440

You Wu,Qi Zhu,Mengya Wang,Mengdie Chen,Ming Chen,Ke Kang,Cai Ning,Yong Shen,Ji Cao,Jiaan Shao,Haiying Zhu,Huilong Dong,Wenteng Chen

{"title":"A Peripheral Sulfonium Moiety Engineering Strategy to Enhance AIEgen-Based Antitumor Photodynamic Therapy","authors":"You Wu,Qi Zhu,Mengya Wang,Mengdie Chen,Ming Chen,Ke Kang,Cai Ning,Yong Shen,Ji Cao,Jiaan Shao,Haiying Zhu,Huilong Dong,Wenteng Chen","doi":"10.1021/acs.jmedchem.6c01440","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.6c01440","url":null,"abstract":"Abstract The therapeutic efficacy of photosensitizers (PSs) strongly depends on their capacity to efficiently generate reactive oxygen species (ROS). Herein, we report a peripheral sulfonium moiety engineering strategy and identify a lead aggregation-induced emission (AIE)-based PS, S12. The sulfonium moiety enhances the photosensitization of S12 primarily by increasing spin−orbit coupling (SOC) and reducing ΔEST, thus boosting ROS generation. Moreover, the sulfonium unit enables S12 to simultaneously produce both Type I and Type II ROS, rendering its photosensitization weakly dependent on O2 concentration. Owing to its cationic character and the inherent amphiphilicity of the AIE core, S12 exhibits dynamic organelle-targeting behavior, initially anchoring to membranes and subsequently accumulating in lipid droplets. Such localization facilitates ROS-triggered ferroptosis, leading to potent in vitro antitumor photodynamic therapy activity and effective tumor suppression in a 4T1 mouse model. Overall, this work provides a rational design strategy to advance AIE-based PSs with enhanced therapeutic potential.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"3 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2026-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149151438","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}

引用次数: 0

Deciphering the Structure−Activity Relationships Underpinning the Linkerology of Bivalent EGFR Inhibitors 破译结构-活性关系，支持二价EGFR抑制剂的连锁学

IF 7.3 1区医学

Journal of Medicinal Chemistry Pub Date : 2026-10-09 DOI: 10.1021/acs.jmedchem.6c02714

Kishan B. Patel,Ishola A. Akinwumi,Tess M. Weber,Monica R. MacDonald,Stephen J. Collins,Surbhi P. Chitnis,Colton L. Zack,Blessing C. Ogboo,Nader N. Nasief,Emily A. Ouellette,Omobolanle A. Abidakun,Michael J. Eck,Asher L. Brandt,Florian Wittlinger,Stefan A. Laufer,Hung T. Nguyen,David E. Heppner

{"title":"Deciphering the Structure−Activity Relationships Underpinning the Linkerology of Bivalent EGFR Inhibitors","authors":"Kishan B. Patel,Ishola A. Akinwumi,Tess M. Weber,Monica R. MacDonald,Stephen J. Collins,Surbhi P. Chitnis,Colton L. Zack,Blessing C. Ogboo,Nader N. Nasief,Emily A. Ouellette,Omobolanle A. Abidakun,Michael J. Eck,Asher L. Brandt,Florian Wittlinger,Stefan A. Laufer,Hung T. Nguyen,David E. Heppner","doi":"10.1021/acs.jmedchem.6c02714","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.6c02714","url":null,"abstract":"Abstract Linking small molecules that bind adjacent sites on a target is a promising strategy for developing compounds with tight binding affinities. ATP-allosteric bivalent inhibitors (AABIs) of the epidermal growth factor receptor (EGFR) have provided new insights into efficient linker design where large potency gains can be achieved through particular design scenarios. In this work, we systematically evaluated the structure−activity relationships of target molecules to better understand the most effective approach to maximizing potency through linker optimization. Our results show that linker length and points of connection are both important strategies for significant potency enhancements. Structures and simulations indicate that maximal flexibility is likely the most important design criterion for linking molecules that occupy adjacent pockets, as modeled by the EGFR kinase domain. These studies provide a general framework for the rational design of linkers broadly relevant to fragment-based drug discovery and a number of related scenarios in medicinal chemistry.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"11 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2026-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149151436","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}

引用次数: 0

Design, Synthesis, and Pharmacological Profiling of Serine/Threonine Kinase 33 (STK33) Inhibitors for Nonhormonal Male Contraception 用于非激素男性避孕的丝氨酸/苏氨酸激酶33 （STK33）抑制剂的设计、合成和药理分析

IF 7.3 1区医学

Journal of Medicinal Chemistry Pub Date : 2026-10-09 DOI: 10.1021/acs.jmedchem.6c00790

Angela F. Ku,Hai Minh Ta,Yong Wang,Geena Kaown,Kiran L. Sharma,Kurt M. Bohren,Xuan Qin,Jian Wang,Ravikumar Jimmidi,Chandrashekhar Madasu,Qi Miao,Banumathi Sankaran,Mingxing Teng,Zhi Tan,Srinivas Chamakuri,Feng Li,Damian W. Young,Choel Kim,Martin M. Matzuk

{"title":"Design, Synthesis, and Pharmacological Profiling of Serine/Threonine Kinase 33 (STK33) Inhibitors for Nonhormonal Male Contraception","authors":"Angela F. Ku,Hai Minh Ta,Yong Wang,Geena Kaown,Kiran L. Sharma,Kurt M. Bohren,Xuan Qin,Jian Wang,Ravikumar Jimmidi,Chandrashekhar Madasu,Qi Miao,Banumathi Sankaran,Mingxing Teng,Zhi Tan,Srinivas Chamakuri,Feng Li,Damian W. Young,Choel Kim,Martin M. Matzuk","doi":"10.1021/acs.jmedchem.6c00790","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.6c00790","url":null,"abstract":"Abstract Serine/threonine kinase 33 (STK33) is a male germ-specific nonhormonal contraceptive target that is both genetically and chemically validated. Building on our previously reported reversible male contraceptive inhibitor, CDD-2807, we conducted systematic structure−activity relationship (SAR) and structure−property relationship (SPR) studies on the 3-(biphenylethynyl)-1H-indazole scaffold to address key drug development liabilities, most notably poor kinetic solubility. These efforts identified CDD-3094, which exhibits a balanced profile characterized by retained nanomolar cellular potency, &gt;100 μM kinetic solubility, comparable metabolic stability, reduced human ether-à-go-go-related gene (hERG) channel inhibition, and a favorable cellular kinase profile, with 278 of 300 kinases (92.7%) displaying &lt;30% occupancy at 1000 nM. Leveraging X-ray crystallography of the STK33/CDD-3094 complex, we performed structure-based modifications to specifically target the primary off-target liability, CDC-like kinase 4 (CLK4). This work culminated in the discovery of compound 40, which achieved 446-fold biochemical selectivity for STK33 over CLK4. While its cellular potency is attenuated to &gt;1 μM, this analog provides a valuable biochemical tool for investigating STK33 selectivity and highlights the challenges of balancing kinase discrimination with intracellular activity. Collectively, these studies establish a foundation for developing soluble STK33 inhibitors, facilitating further preclinical refinement of nonhormonal male contraceptives.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"9 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2026-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149151477","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}

引用次数: 0