Cyanoquinoline HIPK4 inhibitors open a route to non-hormonal male contraception
- HIPK4 is a spermatid-specific kinase needed for sperm head shaping, making it a candidate non-hormonal contraceptive target.
- A cyanoquinoline series gave potent, HIPK4-selective inhibitors, selective within the HIPK family and across the kinome.
- Some compounds also altered HIPK4 proteostasis in spermatids, causing insoluble aggregates and recruiting the autophagy receptor TAX1BP1.
💡 Points
A selective kinome-wide profile from a first series is what a probe needs, and the unexpected proteostasis effect is the intriguing bit: it hints at a degrader-like mode that could be tuned. For contraception the bar is brutal, though, with reversibility and long-term safety to prove.
Small-Molecule Modulators of HIPK4 Activity and Proteostasis ↗