Macrocyclic pyrazolotriazine CDK7 inhibitor combines kinome-wide selectivity with oral exposure
- Structure-based optimization of a 17-membered macrocyclic pyrazolo-triazine scaffold gave a potent CDK7 inhibitor.
- It showed no significant off-target activity across a panel of more than 400 kinases, addressing the poor selectivity of earlier CDK7 inhibitors.
- In cells it caused cell-cycle arrest, suppressed transcription and lowered c-Myc, especially in triple-negative breast cancer lines, with oral bioavailability and linear PK.
💡 Points
A clean result across 400+ kinases is rare for CDK7, where the covalent field has leaned on THZ-type warheads. A non-covalent macrocycle that is also orally exposed is the profile I'd actually want to pick up for a transcriptional-addiction indication. The open question is on-target toxicity, since selectivity among kinases won't spare you CDK7's role in normal transcription.