دورية أكاديمية
Reversible male contraception by targeted inhibition of serine/threonine kinase 33.
| العنوان: | Reversible male contraception by targeted inhibition of serine/threonine kinase 33. |
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| المؤلفون: | Ku AF; Center for Drug Discovery, Department of Pathology & Immunology, Baylor College of Medicine, Houston, TX 77030, USA., Sharma KL; Center for Drug Discovery, Department of Pathology & Immunology, Baylor College of Medicine, Houston, TX 77030, USA., Ta HM; Center for Drug Discovery, Department of Pathology & Immunology, Baylor College of Medicine, Houston, TX 77030, USA.; Verna and Marrs McLean Department of Biochemistry and Molecular Pharmacology, Baylor College of Medicine, Houston, TX 77030, USA., Sutton CM; Center for Drug Discovery, Department of Pathology & Immunology, Baylor College of Medicine, Houston, TX 77030, USA., Bohren KM; Center for Drug Discovery, Department of Pathology & Immunology, Baylor College of Medicine, Houston, TX 77030, USA., Wang Y; Center for Drug Discovery, Department of Pathology & Immunology, Baylor College of Medicine, Houston, TX 77030, USA., Chamakuri S; Center for Drug Discovery, Department of Pathology & Immunology, Baylor College of Medicine, Houston, TX 77030, USA., Chen R; Center for Drug Discovery, Department of Pathology & Immunology, Baylor College of Medicine, Houston, TX 77030, USA., Hakenjos JM; Center for Drug Discovery, Department of Pathology & Immunology, Baylor College of Medicine, Houston, TX 77030, USA., Jimmidi R; Center for Drug Discovery, Department of Pathology & Immunology, Baylor College of Medicine, Houston, TX 77030, USA., Kent K; Center for Drug Discovery, Department of Pathology & Immunology, Baylor College of Medicine, Houston, TX 77030, USA.; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA., Li F; Center for Drug Discovery, Department of Pathology & Immunology, Baylor College of Medicine, Houston, TX 77030, USA.; Verna and Marrs McLean Department of Biochemistry and Molecular Pharmacology, Baylor College of Medicine, Houston, TX 77030, USA., Li JY; Center for Drug Discovery, Department of Pathology & Immunology, Baylor College of Medicine, Houston, TX 77030, USA., Ma L; Center for Drug Discovery, Department of Pathology & Immunology, Baylor College of Medicine, Houston, TX 77030, USA., Madasu C; Center for Drug Discovery, Department of Pathology & Immunology, Baylor College of Medicine, Houston, TX 77030, USA., Palaniappan M; Center for Drug Discovery, Department of Pathology & Immunology, Baylor College of Medicine, Houston, TX 77030, USA., Palmer SS; Center for Drug Discovery, Department of Pathology & Immunology, Baylor College of Medicine, Houston, TX 77030, USA., Qin X; Center for Drug Discovery, Department of Pathology & Immunology, Baylor College of Medicine, Houston, TX 77030, USA., Robers MB; Promega Corporation, Madison, WI 53711, USA., Sankaran B; Molecular Biophysics and Integrated Bioimaging, Berkeley Center for Structural Biology, Lawrence Berkeley National Laboratory, Berkeley, CA 94720, USA., Tan Z; Center for Drug Discovery, Department of Pathology & Immunology, Baylor College of Medicine, Houston, TX 77030, USA.; Verna and Marrs McLean Department of Biochemistry and Molecular Pharmacology, Baylor College of Medicine, Houston, TX 77030, USA., Vasquez YM; Center for Drug Discovery, Department of Pathology & Immunology, Baylor College of Medicine, Houston, TX 77030, USA., Wang J; Center for Drug Discovery, Department of Pathology & Immunology, Baylor College of Medicine, Houston, TX 77030, USA., Wilkinson J; Promega Corporation, Madison, WI 53711, USA., Yu Z; Center for Drug Discovery, Department of Pathology & Immunology, Baylor College of Medicine, Houston, TX 77030, USA., Ye Q; Center for Drug Discovery, Department of Pathology & Immunology, Baylor College of Medicine, Houston, TX 77030, USA., Young DW; Center for Drug Discovery, Department of Pathology & Immunology, Baylor College of Medicine, Houston, TX 77030, USA.; Verna and Marrs McLean Department of Biochemistry and Molecular Pharmacology, Baylor College of Medicine, Houston, TX 77030, USA., Teng M; Center for Drug Discovery, Department of Pathology & Immunology, Baylor College of Medicine, Houston, TX 77030, USA.; Verna and Marrs McLean Department of Biochemistry and Molecular Pharmacology, Baylor College of Medicine, Houston, TX 77030, USA., Kim C; Center for Drug Discovery, Department of Pathology & Immunology, Baylor College of Medicine, Houston, TX 77030, USA.; Verna and Marrs McLean Department of Biochemistry and Molecular Pharmacology, Baylor College of Medicine, Houston, TX 77030, USA., Matzuk MM; Center for Drug Discovery, Department of Pathology & Immunology, Baylor College of Medicine, Houston, TX 77030, USA.; Verna and Marrs McLean Department of Biochemistry and Molecular Pharmacology, Baylor College of Medicine, Houston, TX 77030, USA.; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA. |
| المصدر: | Science (New York, N.Y.) [Science] 2024 May 24; Vol. 384 (6698), pp. 885-890. Date of Electronic Publication: 2024 May 23. |
| نوع المنشور: | Journal Article |
| اللغة: | English |
| بيانات الدورية: | Publisher: American Association for the Advancement of Science Country of Publication: United States NLM ID: 0404511 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1095-9203 (Electronic) Linking ISSN: 00368075 NLM ISO Abbreviation: Science Subsets: MEDLINE |
| أسماء مطبوعة: | Publication: Original Publication: New York, N.Y. : [s.n.] 1880- |
| مواضيع طبية MeSH: | Contraceptive Agents, Male*/chemistry , Contraceptive Agents, Male*/pharmacology , Protein Kinase Inhibitors*/pharmacology , Protein Kinase Inhibitors*/chemistry , Protein Serine-Threonine Kinases*/antagonists & inhibitors , Protein Serine-Threonine Kinases*/chemistry , Small Molecule Libraries*/chemistry , Small Molecule Libraries*/pharmacology , Contraception*/methods, Animals ; Humans ; Male ; Mice ; Blood-Testis Barrier/metabolism ; Testis/drug effects ; Structure-Activity Relationship |
| مستخلص: | Men or mice with homozygous serine/threonine kinase 33 ( STK33 ) mutations are sterile owing to defective sperm morphology and motility. To chemically evaluate STK33 for male contraception with STK33-specific inhibitors, we screened our multibillion-compound collection of DNA-encoded chemical libraries, uncovered potent STK33-specific inhibitors, determined the STK33 kinase domain structure bound with a truncated hit CDD-2211, and generated an optimized hit CDD-2807 that demonstrates nanomolar cellular potency (half-maximal inhibitory concentration = 9.2 nanomolar) and favorable metabolic stability. In mice, CDD-2807 exhibited no toxicity, efficiently crossed the blood-testis barrier, did not accumulate in brain, and induced a reversible contraceptive effect that phenocopied genetic STK33 perturbations without altering testis size. Thus, STK33 is a chemically validated, nonhormonal contraceptive target, and CDD-2807 is an effective tool compound. |
| التعليقات: | Comment in: Science. 2024 May 24;384(6698):849-850. doi: 10.1126/science.adp6432. (PMID: 38781397) |
| المشرفين على المادة: | 0 (Contraceptive Agents, Male) 0 (Protein Kinase Inhibitors) EC 2.7.11.1 (Protein Serine-Threonine Kinases) 0 (Small Molecule Libraries) EC 2.7.11.1 (STK33 protein, human) EC 2.7.11.1 (Stk33 protein, mouse) |
| تواريخ الأحداث: | Date Created: 20240523 Date Completed: 20240523 Latest Revision: 20240606 |
| رمز التحديث: | 20240607 |
| DOI: | 10.1126/science.adl2688 |
| PMID: | 38781365 |
| قاعدة البيانات: | MEDLINE |
Full Text Finder | تدمد: | 1095-9203 |
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| DOI: | 10.1126/science.adl2688 |