# Target Engagement

> **NIH NIH P50** · WEILL MEDICAL COLL OF CORNELL UNIV · 2024 · $254,570

## Abstract

Target Engagement Core
Soluble adenylyl cyclase (sAC: ADCY10) is a nonhormonal target, genetically and pharmacologically
validated to be essential for male fertility. The goal of this Weill Cornell Medicine Contraception Research
Center (WCM-CRC) is to develop acutely acting sAC inhibitors into on-demand birth control pills which a
man would take shortly before sex, only when, and as often as, needed. Using an established, structure-
based drug design workflow consisting of (a) modeling and medicinal chemistry; (b) crystallography and
structure determination of inhibitor-human sAC complexes; and (c) a battery of in vitro biochemical assays
measuring potency, efficacy, and specificity, we successfully developed a series of potent, specific, and
drug-like sAC inhibitors suitable for in vivo interrogation of sAC pharmaceutical potential. In preclinical
proof-of-concept experiments in mice, a `tool' compound rendered male mice temporarily infertile and
identified long residence time on sAC protein as an essential efficacy-defining feature. Thus, we now
augment our established workflow with biophysical studies directly assessing binding kinetics. We
centralize these biochemical, biophysical, and crystallographic studies examining potency, selectivity,
binding kinetics, and molecular interactions of sAC inhibitors into a `closed' technical core. This in vitro
Target Engagement core will support all three Projects in the WCM-CRC. While characterization of newly
designed analogs in Projects 1 and 3 will constitute its major use, it will also be used to confirm the in vitro
efficacy of advanced leads synthesized in larger quantities for the studies in Project 2.

## Key facts

- **NIH application ID:** 10904989
- **Project number:** 5P50HD113015-02
- **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:** 2024
- **Award amount:** $254,570
- **Award type:** 5
- **Project period:** 2023-08-10 → 2026-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10904989

## Citation

> US National Institutes of Health, RePORTER application 10904989, Target Engagement (5P50HD113015-02). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10904989. Licensed CC0.

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