With the advent of specific kinase inhibitors like imatinib, further development of small molecule kinase inhibitors has been a promising avenue to combat cancer. In particular, cyclin-dependent kinase 2 (Cdk2) has been a promising anti-cancer target, as it is normally activated by cyclin E to proceed through the cell cycle at the G1/S phase transition, and is hyperactivated in diseases such as ovarian, breast, and colorectal cancers. Additionally, Cdk2 knock-out mice are viable, so healthy tissue would ideally be unaffected by selective treatment. Historically, developed Cdk2 inhibitors bind the active site, leading to many off-target effects due to the homology of the ATP-binding site among kinases, especially other Cdk enzymes. Our group previously discovered that the dye 8-anilino-1-naphthalene sulfonic acid (ANS) inhibits Cdk2 by binding an unrecognized allosteric pocket of the enzyme, renewing efforts to target this kinase in a specific manner. Using this discovery, virtual and high-throughput screens targeting the allosteric pocket were conducted, yielding a novel scaffold. X-ray crystallography revealed this scaffold bound to the allosteric pocket of Cdk2 and causes it to adopt a novel inhibited conformation. Lead optimization has yielded three allosteric inhibitors with double-digit nanomolar affinity towards Cdk2. Additionally, this series inhibits the kinase in a manner that is negatively cooperative with cyclin binding, a protein-protein activation crucial for Cdk2 activity. To our knowledge, our lead inhibitors are the tightest-binding allosteric inhibitors of Cdk2 discovered to date. Additionally, its disruption of cyclin binding represents a novel mode of kinase inhibition.

Allosteric inhibitors of cyclin-dependent kinase 2 (Cdk2) disrupt the Cdk2-cyclin complex

Macromolecular Chemistry: The Second Century

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ACS Spring 2020 National Meeting & Expo

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