# On-Demand Pharmacological Contraception by Blocking ADCY 10

> **NIH NIH P50** · WEILL MEDICAL COLL OF CORNELL UNIV · 2021 · $1,982,625

## Abstract

Overall
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. This proposed Contraception Research Center
(CRC) has a singular scientific theme; to identify the safest and most efficacious means for
blocking sAC in vivo to achieve an on-demand contraceptive pill. The overall design of the CRC
leverages the already successful interdisciplinary team comprised of expertise in sAC
pharmacology and biochemistry (Drs. Levin & Buck), sAC structural biology (Dr. Steegborn), and
medicinal chemistry and drug development [Dr. Meinke & his team at the Tri-Institutional
Therapeutics Discovery Institute (TDI)]. To complete the CRC, we add to this team an Andrology
Core (led by Drs. Lamb & Schlegel) for assessing efficacy against human sperm. In the first two
Projects, we focus on sAC catalytic domain inhibitors with the expectation that pharmacokinetic
parameters can be optimized to balance efficacy with minimal adverse effects. In the first project,
we will perform in vivo studies of efficacy, safety, and pharmacokinetics to refine the existing
scaffold of sAC inhibitors with proven efficacy in mice into preclinical development candidates
suitable for development partners to apply for an FDA Investigational New Drug (IND). The goal
of Project 2 is to develop additional leads, based upon recombination and optimization of moieties
from distinct, but structurally and biochemically validated scaffolds, which would be suitable for
subjecting to the in vivo studies proposed in Project 1. The third project proposes a high
throughput screening strategy to identify inhibitors targeting regulatory domains of sAC isoforms
enriched in sperm. Such inhibitors should exhibit diminished side effects. The ultimate goal of
Project 3 is to identify hits which will be developed using the same principles and methods outlined
in Projects 1 and 2. The overall hypothesis tested in this CRC is that sAC inhibitors can be
designed which can be appropriately dosed to block sperm functions while minimizing undesirable
side effects.

## Key facts

- **NIH application ID:** 10144835
- **Project number:** 5P50HD100549-03
- **Recipient organization:** WEILL MEDICAL COLL OF CORNELL UNIV
- **Principal Investigator:** JOCHEN BUCK
- **Activity code:** P50 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $1,982,625
- **Award type:** 5
- **Project period:** 2019-09-12 → 2022-09-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10144835

## Citation

> US National Institutes of Health, RePORTER application 10144835, On-Demand Pharmacological Contraception by Blocking ADCY 10 (5P50HD100549-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10144835. Licensed CC0.

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