Reversible male contraception by targeted inhibition of serine/threonine kinase 33-Reference-Cited by-同舟云学术

Reversible male contraception by targeted inhibition of serine/threonine kinase 33

Published:2024-05-24 Issue:6698 Volume:384 Page:885-890
ISSN:0036-8075
Container-title:Science
language:en
Short-container-title:Science

Author:

Ku Angela F.¹^ORCID,Sharma Kiran L.¹^ORCID,Ta Hai Minh¹²^ORCID,Sutton Courtney M.¹^ORCID,Bohren Kurt M.¹^ORCID,Wang Yong¹,Chamakuri Srinivas¹^ORCID,Chen Ruihong¹,Hakenjos John M.¹^ORCID,Jimmidi Ravikumar¹^ORCID,Kent Katarzyna¹³^ORCID,Li Feng¹²^ORCID,Li Jian-Yuan¹^ORCID,Ma Lang¹,Madasu Chandrashekhar¹^ORCID,Palaniappan Murugesan¹^ORCID,Palmer Stephen S.¹,Qin Xuan¹^ORCID,Robers Matthew B.⁴,Sankaran Banumathi⁵^ORCID,Tan Zhi¹²,Vasquez Yasmin M.¹^ORCID,Wang Jian¹^ORCID,Wilkinson Jennifer⁴^ORCID,Yu Zhifeng¹^ORCID,Ye Qiuji¹^ORCID,Young Damian W.¹²,Teng Mingxing¹²^ORCID,Kim Choel¹²^ORCID,Matzuk Martin M.¹²³^ORCID

Affiliation:

1. Center for Drug Discovery, Department of Pathology & Immunology, Baylor College of Medicine, Houston, TX 77030, USA.

2. Verna and Marrs McLean Department of Biochemistry and Molecular Pharmacology, Baylor College of Medicine, Houston, TX 77030, USA.

3. Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.

4. Promega Corporation, Madison, WI 53711, USA.

5. Molecular Biophysics and Integrated Bioimaging, Berkeley Center for Structural Biology, Lawrence Berkeley National Laboratory, Berkeley, CA 94720, USA.

Abstract

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.

Publisher

American Association for the Advancement of Science (AAAS)

Link

https://www.science.org/doi/pdf/10.1126/science.adl2688

Reference76 articles.

1. Available from https://www.worldometers.info/world-population/#milestones.

2. Toward a rapid and reversible male pill

3. Available from: http://consensusforaction.stanford.edu/see-scientific-consensus/consensus_english.pdf.

4. A brief history and future prospects of contraception

5. As the world grows: contraception in the 21st century

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