Development of small molecule inhibitors of RBM46 as novel male contraceptives

The National Institute of Child Health and Human Development awarded $2.252 million to the University of Texas at San Antonio on February 11, 2026, under the Child Health and Human Development Extramural Research program (CFDA 93.865) to develop small molecule inhibitors of RBM46 as oral, non-hormonal male contraceptives. The project targets RBM46, a germ cell-specific RNA binding protein essential for spermatogenesis, with the goal of creating reversible male contraception by blocking spermatogenesis at the differentiating spermatogonial stage. Work includes computer-aided drug discovery and high-throughput screening of RBM46 small molecular degraders, validation of hits through biochemical and biophysical assays, and development and characterization of RBM46 PROTACs using validated RBM46 binders in collaboration with medicinal chemistry cores.

Place of performance is San Antonio, Texas, with a period of performance through January 31, 2029. The award leverages drug screening and development expertise at UTSA and UT Health San Antonio, male reproduction and spermatogenesis expertise at UTSA and East Carolina University, proximity to an NIH-designated marmoset breeding colony at the Southwest National Primate Research Center, and published expertise in single-cell genomics and spermatogonial stem cell transplantation.

UT Health Science Center at San Antonio (sub-award R33HD114223-1000007319, obligated June 12, 2026) performs computer-aided drug discovery, high-throughput screening, and hit validation through biochemical and biophysical assays. East Carolina University's Brody School of Medicine (sub-award R33HD114223-1000007320, obligated June 5, 2026) conducts in vitro and in vivo mouse experiments, including primary cell culture work to validate PROTAC degradation of endogenous RBM46 in male germ cells and, pending R33 award determination, in vivo efficacy, safety, and reversibility assessment in live mice.

Abstract

Development of novel contraceptive strategies is central to the mission of the contraceptive research branch of the nichd. This goal is driven by a global need for effective contraceptive methods to address: 1) the glut of unintended pregnancies (~45% of US pregnancies in 2011); 2) the high rate of elective abortion (1.15M unintended pregnancies ended in abortion in 2011 in the US); and 3) the high risk of maternal mortality (~830 women/day worldwide DIE due to pregnancy or childbirth complications). In a search for novel male contraceptive drug targets, we identified RBM46, which is a germ cell-specific RNA binding protein expressed by germ cells on the basement membrane of seminiferous tubules (outside the blood-testis-barrier), and is essential for spermatogenesis. Indeed, RBM46 knockout mice are sterile and have no other phenotype, raising the distinct possibility that targeting RBM46 could lead to safe and effective male contraception by blocking spermatogenesis at the differentiating spermatogonial stage. Thus, we propose to develop drugs that target degradation of RBM46 as a means of oral, non-hormonal male contraception, which will significantly advance additional safe and reversible options for male contraception towards the clinic. Specifically, we will combine: 1) exceptional expertise in drug screening and development at utsa and UT health SAN antonio; 2) leading expertise in male reproduction, spermatogenesis, and infertility at utsa and ECU; 3) close proximity to one of two NIH-designated marmoset breeding colonies, maintained at the southwest national primate research center; 4) growing and ongoing experience collecting and assessing marmoset sperm; 5) published experience in the use of cutting- edge single-cell genomics to assess normality of spermatogenic cell types; and 6) documented expertise with spermatogonial stem cell (SSC) transplantation. In aim 1, we will identify small molecules that bind RBM46 and could be used to develop protacs. In aim 2, we will produce initial RBM46 protacs and validate that they degrade the protein in vitro. In aim 3, we will use medicinal chemistry to optimize the drug-like characteristics of top validated RBM46 protacs. In aims 4 and 5, we will determine whether optimized RBM46 protacs induce reversible contraception in vivo using mice and marmosets, respectively. Together, these aims are designed to advance RBM46 degradation as a novel strategy to achieve reversible, non-hormonal male contraception and provide key results to justify further preclinical investigation and eventual commercialization.