Design and Synthesis of Novel Macrocyclic Derivatives as Potent and Selective Cyclin-Dependent Kinase 7 Inhibitors

The duality of function (cell cycle regulation and gene
transcription)
of cyclin-dependent kinase 7 (CDK7) makes it an attractive oncology
target and the discovery of CDK7 inhibitors has been a long-term pursuit
by academia and pharmaceutical companies. However, achieving selective
leading compounds is still difficult owing to the similarities among
the ATP binding pocket. Herein, we detail the design and synthesis
of a series of macrocyclic derivatives with pyrazolo­[1,5-a]-1,3,5-triazine core structure as potent and selective CDK7 inhibitors.
The diverse manners of macrocyclization led to distinguished selectivity
profiles of the CDK family. Molecular dynamics (MD) simulation explained
the binding difference between 15- and 16-membered macrocyclic compounds. Further optimization generated compound 37 exhibiting good CDK7 inhibitory activity and high selectivity
over other CDKs. This work clearly demonstrated macrocyclization is
a versatile method to finely tune the selectivity profile of small
molecules and MD simulation can be a valuable tool in prioritizing
designs of the macrocycle.