Reversible male contraception by targeted inhibition of serine/threonine kinase 33.
Science
; 384(6698): 885-890, 2024 May 24.
Article
em En
| MEDLINE
| ID: mdl-38781365
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.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Proteínas Serina-Treonina Quinases
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Anticoncepção
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Anticoncepcionais Masculinos
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Inibidores de Proteínas Quinases
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Bibliotecas de Moléculas Pequenas
Limite:
Animals
/
Humans
/
Male
Idioma:
En
Revista:
Sci. (N.Y., N.Y.)
/
Science
Ano de publicação:
2024
Tipo de documento:
Article
País de afiliação:
Estados Unidos