PROJECT SUMMARY/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.