Many tumor types are critically dependent on transcription and upregulated gene expression for maintenance of their oncogenic state. Oncogenic transcription factors use the general transcriptional machinery to drive tumorigenesis, but targeting transcription factors therapeutically has proven highly challenging. Consequently, targeting key enzymatic regulators of the transcriptional machinery is an attractive strategy for cancer therapy. One such co-factor is cyclin-dependent kinase 7 (CDK7), which modulates transcription by phosphorylating the C-terminal domain of RNA polymerase II (RNAPII). Superenhancer-driven oncogenes, e.g. c-Myc, Myb or Mcl1, show increased dependence on CDK7 mediated transcription. However, the discovery of selective inhibitors of CDK7 has been hampered by the high sequence and structural similarities of the kinase domain of CDK family members. As others in the field we reasoned that the presence of a cysteine residue (Cys312) outside but proximal to the canonical ATP-pocket in CDK7, presented an attractive opportunity for covalent targeting. Our strategy focused on the discovery of selective irreversible ATP-competitive inhibitors that also bind covalently to the protein – affording the potential to achieve high levels of biochemical and cellular selectivity together with a sustained in vivo response even in the presence of rapid systemic clearance. We will present the discovery and evolution of potent, selective and orally bioavailable irreversible covalent CDK7 inhibitors, displaying potent CDK7 occupancy, downregulation of super-enhancer regulated genes and tumor growth inhibition in murine xenograft tumors in vivo.

Potent, selective and bioavailable covalent inhibitors of CDK7

Fall 2022 abstracts, posters, and presentations will launch in mid-September.

ACS Fall 2022

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.