# Development of regulatory domain inhibitors of ADCY10

> **NIH NIH P50** · WEILL MEDICAL COLL OF CORNELL UNIV · 2021 · $357,881

## Abstract

Project 3
Freshly ejaculated mammalian sperm are unable to fertilize an egg. They acquire fertilizing
capacity in the hours following ejaculation, as they pass through the female reproductive tract, in
a process known as capacitation. Soluble adenylyl cyclase (sAC: ADCY10) is a non-hormonal
target essential for sperm capacitation and male fertility. Pharmacological sAC inhibitors block
sperm functions in vitro and two distinct sAC knockout (KO) mouse strains exhibit male-specific
sterility without exhibiting other overt phenotypes. The overall hypothesis tested in this
Contraception Research Center (CRC) is that sAC inhibitors can be designed which can be
appropriately dosed to block sperm functions while minimizing undesirable side effects. We have
recently identified small molecule activators of sAC which function via regulatory domains outside
sAC’s catalytic core. These activators selectively stimulate isoforms of sAC enriched in sperm. In
this Contraception Development Research Project, we hypothesize that a new class of inhibitors,
which binds to these regulatory domains, will prevent capacitation by selectively inhibiting sAC
functions in sperm. Regulatory-domain targeting sAC inhibitors would produce fewer undesirable
side effects. In this Project, we propose a high throughput strategy to identify small molecules
which block the activation of sperm sAC and prevent capacitation. Suitable regulatory domain
sAC inhibitors will be subjected to the pipeline of refinement cycles and in vivo studies described
in Projects 1 and 2 of this CRC. The ultimate goal of this Project is to develop inhibitors selective
for sAC isoforms in sperm as lead compounds for oral, non-hormonal contraceptives.

## Key facts

- **NIH application ID:** 10144842
- **Project number:** 5P50HD100549-03
- **Recipient organization:** WEILL MEDICAL COLL OF CORNELL UNIV
- **Principal Investigator:** LONNY R LEVIN
- **Activity code:** P50 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $357,881
- **Award type:** 5
- **Project period:** 2019-09-12 → 2022-09-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10144842

## Citation

> US National Institutes of Health, RePORTER application 10144842, Development of regulatory domain inhibitors of ADCY10 (5P50HD100549-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10144842. Licensed CC0.

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