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

> **NIH NIH R01** · BAYLOR COLLEGE OF MEDICINE · 2024 · $646,413

## Abstract

PROJECT SUMMARY
The overarching objective of this new R01 grant proposal is to perform preclinical drug development
studies to create potent, selective, metabolically stable, and peripherally restricted serine/threonine
kinase 33 (STK33) inhibitors that can provide a foundation as first-in-class non-hormonal contraceptive
drugs for men. Kinases are key enzymatic targets for drug inhibition in the pharmaceutical industry. However,
only ~70 of the 538 human kinases have FDA-approved inhibitor drugs or drug candidates. Therefore, a vast
number of therapeutic opportunities exist by targeting kinases. A subset of ~160 kinases are poorly understood
or studied and are designated as “dark kinases”. One of these dark kinases is STK33, which is testis-enriched
and expressed in spermatocytes through transformation of spermatids. Stk33 knockout males are sterile
secondary to teratozoospermia and sperm immotility, and men in a single family were discovered to have a
frameshift mutation in the STK33 gene, leading to infertility that phenocopied the knockout mice. Because mice
and men with these STK33 mutations are grossly normal, we hypothesize that STK33 is a pursuable target
with low safety risk for contraceptive inhibition in men. To discover STK33 probe or tool compounds for in vivo
chemical perturbation of STK33 function, we used DNA-Encoded Chemistry Technology (DEC-Tec) and
screened 3.9 billion unique DNA-molecules with human STK33 to identify high affinity binders. We created
several potent and selective kinase inhibitors, including CDD-2807, which showed picomolar biochemical
inhibition of STK33 (Kd = 20 pM) and nanomolar cellular inhibition of STK33 (IC50 = 9 nM) versus other kinases.
In a contraceptive fertility trial in mice, CDD-2807 induced reversible contraceptive effects in male mice without
causing any observable toxic effects or greatly altering testis size. Thus, our studies prove that STK33 is a
genetically and chemically validated contraceptive target and that CDD-2807 is a favorable lead chemical
probe suitable for in vivo studies of STK33 function. The Specific Aims are: 1) Use DEC-Tec screens,
medicinal chemistry, and X-ray crystallography to create more potent, selective, and metabolically stable
STK33 inhibitors; 2) Assess the metabolic and pharmacokinetic properties, tissue distribution, and safety of
STK33 inhibitors in mice and non-human primates; and 3) Evaluate the contraceptive effects of optimized
STK33 lead inhibitors in mice and non-human primates. Based on our preliminary studies and our
outstanding interdisciplinary team, which works at the intersection of mouse and non-human primate
reproductive biology, chemical biology, medicinal chemistry, structural biology, drug metabolism, and
pharmaceutical discovery, these R01 studies are highly feasible, will allow us to create optimized lead
inhibitors of STK33 for an Investigational New Drug application, and will address an unmet medical
need for male contraceptive therapeutics.

## Key facts

- **NIH application ID:** 10942775
- **Project number:** 1R01HD115711-01
- **Recipient organization:** BAYLOR COLLEGE OF MEDICINE
- **Principal Investigator:** MARTIN M. MATZUK
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $646,413
- **Award type:** 1
- **Project period:** 2024-08-01 → 2029-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10942775

## Citation

> US National Institutes of Health, RePORTER application 10942775, Reversible male contraception by inhibition of serine/threonine kinase 33 (1R01HD115711-01). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10942775. Licensed CC0.

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