4-Aminoquinazoline PKMYT1 inhibitors cut H-bond donors for CCNE1-amplified tumors
- A hydrogen-bond donor-to-acceptor conversion was used to lower the donor count of a 4-aminoquinazoline PKMYT1 series and improve drug-likeness.
- Lead 12f was a nanomolar enzyme inhibitor, potent in OVCAR-3 ovarian cells and synergistic with PARP inhibitors.
- With acceptable oral PK, it showed efficacy in an OVCAR-3 xenograft and was well tolerated.
💡 Points
Trimming HBDs is a clean, transferable tactic for improving permeability and oral exposure in a kinase series. The PARP-inhibitor synergy is the commercially interesting part, but PKMYT1 is crowded, so I'd check selectivity against other kinases and how 12f compares with the clinical frontrunners.