Research

Research Overview

Research in the Georg group continues to discover male non-hormonal contraceptives and anticancer agents. Highly potent and selective RAR-alpha, dual RAR-alpha/gamma, and RAR gamma selective antagonists have been discovered. A second-generation retinoic acid receptor alpha was about 10 times more potent than YCT-529 and has excellent in vivo potency and reversibility of fertility. Studies also continue to discover allosteric and orthosteric kinase inhibitors for CDK2, CDK11, and TSSK1-3 and inhibitors for the testis-specific BET bromodomain. The discovery of sperm motility inhibitors is pursued by targeting three ion channels critical for fertilization: Na,K-ATPase-4, Slo3 and CatSper.

YCT-529, a selective retinoic acid receptor-alpha antagonist discovered in the Georg group, entered a phase 1a clinical trial as the first non-hormonal male contraceptive in the United Kingdom in December 2023. The clinical trial was completed in June 2024, and no safety concerns were observed. A new phase 1b/2a clinical trial was initiated in 2024 in New Zealand.

 Recent Publications

• Syeda, S.S., Sánchez, G., McDermott J.P, Cheryala, N., Wong, H., Georg, G.I., Blanco, G. Strategies to Develop Na,K-ATPase Inhibitors as Male Contraceptives. Int J Mol Sci. 2025 Jun 12;26(12):5646. doi: 10.3390/ijms26125646. PMID: 40565109; PMCID: PMC12192727.

• Nayyab, S., Gervasi, M.G., Tourzani, D.A., Shamailova, Y., Akizawa, H., Taghavi, M., Cui, W., Fissore, R., Salicioni, A.M., Georg, G.I., Snyder, E., Visconti, P.E. Identification of TSSK1 and TSSK2 as Novel Targets for Male Contraception. Biomolecules. 2025 Apr 18;15(4):601. doi: 10.3390/biom15040601. PMID: 40305308; PMCID: PMC12024862.

• Haque, E., Georg, G.I. Medoxomil Prodrug Strategies. J. Med. Chem. 2025 May 8;68(9):9025-9036. doi: 10.1021/acs.jmedchem.4c02967. Epub 2025 Apr 22. PMID: 40261681.

• Giarolla, J., Holdaway, K.A., Nazari, M., Aiad, L.K., Sarkar, B., Georg, G.I. Targeting Cyclin-dependent Kinase 2 Interactions with Cyclins and Speedy 1 for Cancer and Male Contraception. Future Med. Chem. 2025 Mar;17(5):607-627. doi: 10.1080/17568919.2025.2463868. Epub 2025 Mar 4. PMID: 40034037; PMCID: PMC11901406.

• Jiang, J., Liang, T., Solberg, J., Chan, A., Kalra, P., Shi, R., Pomerantz, W.C.K., Hawkinson, J.E., Schönbrunn, E., Georg, G.I. Macrocyclic Dihydropyridine Analogs as pan-BET BD2-biased Inhibitors. Eur. J. Med. Chem. 2025 Jun 5;290:117504. doi: 10.1016/j.ejmech.2025.117504. Epub 2025 Mar 16. PMID: 40120495; PMCID: PMC11993331.

• Shi, R., Wolgemuth, D.J., Georg, G.I. Development of the Retinoic Acid Alpha-specific Antagonists YCT-529 for Male Contraception: A Brief Review. Contraception, 2025 May;145:110809. doi: 10.1016/j.contraception.2024.110809. Epub 2025 Jan 3. PMID: 39756562; PMCID: PMC11993348.

• Mannowetz, N., Chung, S.W., Maitra, S., Noman, M.A.A., Wong, H.L., Cheryala, N., Bakshi, A., Wolgemuth, D.J., Georg, G.I. Targeting the Retinoid Signaling Pathway with YCT-529 for Effective and Reversible Oral Contraception in Mice and Primates. Commun. Med. 2025 Mar 13;5(1):68. doi: 10.1038/s43856-025-00752-7. PMID: 40082579; PMCID:

• Holdaway, J., Georg, G. An Emerging Target for Male Contraception. Science 2024, 24;384(6698):849-850. doi: 10.1126/science.adp6432. Epub 2024 May 23. PMID: 38781397.

• Noman, M.A.A., Cuellar, R.A.D., Kyzer, J., Cheryala, N., Chung, S.S.S., Holth, A.D., Maitra, S., Naqvi, T., Hawkinson, J.E., Schönbrunn, E., Wong, H., Wolgemuth, D.J., Georg, G.I. Strategies for Developing Retinoic Acid Receptor Alpha-Selective Antagonists as Novel Agents for Male Contraception. Eur. J. Med. Chem. 2023, Dec 5;261:115821. doi: 10.1016/j.ejmech.2023.115821. Epub 2023 Sep 25. PMID: 37776573; PMCID:

• Shameem, M., Bagherpoor, A.J., Nakhi, A., Dosa, P., Georg, G.I., Kassie, F. Mitochondria-targeted Metformin (mitomet) Inhibits Lung Cancer in Cellular Models and in Mice by Enhancing the Generation of Reactive Oxygen Species. Mol Carcinog. 2023 Nov;62(11):1619-1629. doi: 10.1002/mc.23603. Epub 2023 Jul 4. PMID: 37401866; PMCID: PMC10961008.

• Faber, E. B., Tang, J., Roberts, E., Ganeshkumar, S., Sun, L., Wang, N., Rasmussen, D., Majumdar, D., John, K., Yang, A., Khalid, H., Hawkinson, J.E., Levinson, N.M., Schönbrunn, E., Chennathukuzhi, V., Harki. D.A., Georg, G.I. Development of Allosteric and Selective CDK2 Inhibitors for Contraception with Negative Cooperativity to Cyclin Binding. Nat. Commun. 2023 Jun 3;14(1):3213. doi: 10.1038/s41467-023-38732-x. PMID: 37270540; PMCID: PMC10239507.

• Kyzer, J., Chung, S.S.S., Noman, M.A.A., Cuellar, R.A.D., Maitra, S., Naqvi, T., Hawkinson, J., Wolgemuth, D. J., Georg, G. I. Investigation of Retinoic Acid Receptor Alpha Antagonist ER50891 and Analogs in vitro for Potency and Selectivity and in vivo Effects of ER50891 on Spermatogenesis. Arch. Pharm. 2023, Jul;356(7):e2300031. doi: 10.1002/ardp.202300031. Epub 2023 May 8. PMID: 37154197.

• Faber, E. B., Wang, N., John, K., Sun, L., Burban, D., Khalid, H., Wong, H.L., Francis, R., Tian, D., Hong, W.H., Yang, A., Wang, L., Elsaid, M., Khalid, H., Levinson, N.M., Schönbrunn, E., Hawkinson, J.E., Georg, G. I. Screening Through Lead Optimization of High Affinity, Allosteric Cyclin-dependent Kinase 2 (CDK2) Inhibitors as Male Contraceptives that Reduce Sperm Counts in Mice. J. Med. Chem. 2023 Feb 9;66(3):1928-1940. doi: 10.1021/acs.jmedchem.2c01731. Epub 2023 Jan 26. PMID: 36701569; PMCID: PMC11556300.

Recent Presentations

• 2025 C. S. Hamilton Award Lecture, November 6-7, 2025, Department of Chemistry, University of Nebraska, Lincoln, NE.

• Keynote, YCT-529 a Male Contraceptive: The Path from Discovery to the Clinic. 2025 Gordon Research Conference on Organic Reactions and Processes Research Conference, July 20-25, Bryant University, Smith Field, Rhode Island.

• Plenary Lecture, XXI National Meeting of the Spanish Society of Medicinal Chemistry (SEQT). June 15-18, 2025, Seville, Spain.

• Plenary Lecture, Discovery of Kinase Inhibitors and Degraders for Male Contraception. 11th RSC/SCI Symposium on Kinase Inhibitor Design. May 12-13, 2025, Edenborough, UK.

• 2025 National Contraception Meeting: Male Non-hormonal Contraceptive Projects in the Georg group: An Update. April 29, 2025, Durham, North Carolina.

• Targeting Drug-Resistant Breast Cancer with Allosteric Cyclin-dependent Kinase (CDK2) Inhibitors. Breast Cancer SPORE Scientific Series Symposium. Mayo Clinic, Rochester, MN, April 16, 2025.

• 2025 Bristol-Myers Squibb Lecture: Discovery and Development of a Male Pill by Targeting the Retinoid Signaling Pathway with YCT-529 for Effective, Reversible Oral Contraception. April 4, 2025, Department of Chemistry, University of Pennsylvania, PA.

• Plenary Lecture, Development of Allosteric Inhibitors against Cyclin-dependent Kinase 2 (CDK2), Global Trends in Health Technology and Management 2025 (GTHTM-2025), February 15-17, 2025, Global Institute of Pharmaceutical Education and Research (GIPER), Kashipur, India.

• Minnesota Department of Health. Sexual and Reproductive Health Services Meeting.  Male Contraception: An Update. October 7, 2024, Saint Paul, MN.

• International Retinoids Conference VII. FASEB. Discovery of Retinoid Receptor Antagonists for Male Contraception. July 7-11, 2024, Saint Paul, MN.

• Fourth International Congress on Male Contraception. Selective Retinoic Acid Receptor Alpha Antagonists. International Consortium for Male Contraception and Population Council. New York, June 6, 2024.

• Keynote Lecture Chemistry-Biochemistry-Biology Interface Annual Symposium: Retinoic Acid Receptor Antagonists: Chemistry and Biology, Notre Dame University, South Bend, Indiana, May 16, 2024.

• Roland T. Lakey Award. Insights from an Academic Career in Medicinal Chemistry: From Leprosy to Contraception. Eugene Applebaum College of Pharmacy and Health Sciences, Wayne State University, Detroit, MI, April 18, 2024.

• Roland T. Lakey Award. Discovery and Development of a Male Pill: Are We Finally Getting There? Eugene Applebaum College of Pharmacy and Health Sciences, Wayne State University, Detroit, MI, April 18, 2024.

• Keynote address. The Male Pill. Are we There Yet? International Symposium on Global Trends in Health, Technology, and Management (GTHTM-2024), Uttarakhand Technical University, India, March 15, 2024.

• Sydney Archer Lecture. Discovery and Development of a Male Pill: Are We Finally Getting There? Department of Chemistry and Chemical Biology, Rensselaer Polytechnic Institute, Albany, NY, March 12, 2024

• Keynote address. Retinoic Acid Receptor Antagonists for Male Non-hormonal Contraception. Keynote. 2nd International Conference: Paradigm Shift in Health Care Profession, University of Swabi, Anbar, Swabi, Pakistan, March 5, 2024.

• Syeda, S.; Sanchez, G.; Cheryala, N.; McDermott, J.; Liu, Y.; Hawkinson, J. E. Wong, H.; Blanco, G.; Georg. G. I. Targeting Na,K-ATPase Alpha-4 for Male Contraception. Center for Biomedical Research Seminar Series, Population Council, New York, NY, February 27, 2024.

• Syeda, S.; Sanchez, G.; Cheryala, N.; McDermott, J.; Liu, Y.; Hawkinson, J. E. Wong, H.; Blanco, G.; Georg. G. I. Targeting Na,K-ATPase Alpaha-4 for Male Contraception. National Contraception Meeting, Baylor Medical College, Houston, TX, November 13-16, 2023.

• The Male Pill: Are We There Yet? 21st International, 1st Inter-Islamic &33rd National Chemistry Conference (CHEMCON23), Islamabad, Pakistan, October 23-25, 2023.

• The Male Pill: Are We There Yet? 48th National Organic Chemistry Symposium, July 9-13, 2023, University of Notre Dame.

• David Chu Distinguished Lectureship on Drug Discovery, University of Georgia, College of Pharmacy, March 15, 2023. The Male Pill: Are We There Yet?

• UW-Madison/WARF Therapeutics Distinguished Lecture in Drug Discovery, University of Wisconsin, Madison, College of Pharmacy, February 10, 2023. Discovery and Development of a Novel Contraceptive for Men.