Fixing solubility and CLK4 off-target liability in STK33 male-contraceptive indazoles
- SAR and property work on the 3-(biphenylethynyl)-1H-indazole scaffold behind CDD-2807 targeted its poor kinetic solubility.
- CDD-3094 kept nanomolar cellular potency while gaining solubility, lowering hERG liability and showing a clean broad kinase panel.
- A co-crystal structure guided changes against the main off-target CLK4, giving a strongly selective biochemical tool whose cellular potency dropped.
💡 Points
This is a textbook potency-versus-properties trade: solubility fixed in CDD-3094, then selectivity bought at the price of cell activity. For a contraceptive, where the safety bar is far higher than in oncology, the CLK4 discrimination matters more than raw potency; the next step is recovering permeability.