Discovery of a Novel Macrocyclic Noncovalent CDK7 Inhibitor for Cancer Therapy.

Cyclin-dependent kinase 7 (CDK7) is a key regulator of the cell cycle and transcription, making it a promising target for cancer therapy. Although current CDK7 inhibitors have improved in their selectivity and druglike properties, CDK7 inhibitors have failed to progress through clinical development due to severe gastrointestinal and hematotoxic side effects. To mitigate these limitations, we have developed novel, macrocyclic, noncovalent CDK7 hit compounds and using a macrocyclization platform that has optimized these compounds from SY-5609, a leading clinical asset. We conducted extensive structure-activity relationship (SAR) studies to improve their potency, enhance oral bioavailability, and reduce intestinal distribution, which resulted in compound . Compound exhibits potent activity, good ADME properties, and robust antitumor activity in xenograft models as a monotherapy. Notably, compound with lower basicity demonstrated improved Caco-2 permeability, reduced blood/plasma ratio, and reduced intestinal distribution in rats, thus mitigating gastrointestinal and hematotoxic side effects.