# Allosteric CDK2 inhibitor Discovery and Development for Male Contraception

> **NIH NIH R61** · UNIVERSITY OF MINNESOTA · 2020 · $376,172

## Abstract

PROJECT SUMMARY
Testosterone and related analogs have been investigated since the 1960s for male contraception. However, an
unfavorable side effect profile, that includes cardiovascular liabilities has prevented commercialization.
Therefore, the exploration of non-hormonal targets is considered a novel approach to discover contraceptive
agents. Despite this very promising possibility a non-hormonal male contraceptive agent has not entered clinical
trial or progressed towards IND-enabling preclinical development.
Critical to such an approach is the selection of a validated target. In this regard, cyclin-dependent protein kinase
2 (CDK2) is auspicious because CDK2 knockout mice are healthy but sterile. Our central hypothesis is that we
can discover an allosteric CDK2 inhibitor lead and a back-up candidate with a different chemical scaffold in the
R61 Phase of this project. Furthermore, we hypothesize that we can develop an allosteric CDK2 inhibitor ready
for pre-IND development during the R33 Phase.
During the R61 phase we propose to discover an allosteric CDK2 inhibitor series and a back-up series preferably
with a different chemical scaffold based on already structurally characterized compounds (x-ray co-crystals) and
by additional screening. In an iterative fashion, we will optimize and evaluate analogs of existing and new hits
by structure-based drug design. Hits will be optimized by using allosteric site binding assays, CDK2 enzyme
inhibition assays, ITC, HSQC NMR, X-ray co-crystal structures, kinase selectivity screens, evaluation of
physicochemical properties, in vitro ADMET assays and biomarkers in testis explant mouse model.
For the R33 Phase, we plan to develop an allosteric CDK2 inhibitor that is ready for pre-IND development. This
lead compound should possess selectivity over other kinases, be orally bioavailable, and exhibit reversible
meiotic biomarker expression. A back-up compound preferably from a different chemical series will also be
progressed to the in vivo oral proof-of-concept stage. Both objectives will be achieved by continuing compound
optimization. Promising compounds will be investigated for complete pharmacokinetic properties, off-target
effects, and in vivo proof of concept.

## Key facts

- **NIH application ID:** 10018520
- **Project number:** 5R61HD099743-02
- **Recipient organization:** UNIVERSITY OF MINNESOTA
- **Principal Investigator:** Vargheese Mani Chennathukuzhi
- **Activity code:** R61 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $376,172
- **Award type:** 5
- **Project period:** 2019-09-13 → 2021-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10018520

## Citation

> US National Institutes of Health, RePORTER application 10018520, Allosteric CDK2 inhibitor Discovery and Development for Male Contraception (5R61HD099743-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10018520. Licensed CC0.

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