Our Science

RLY-2139 is designed to be an oral, small molecule, potent and selective inhibitor of CDK2 that spares other CDKs.

Cyclin-dependent kinases (known as CDKs) are critical regulators of cell division and CDK 4/6 inhibitors have validated targeting the CDK family in breast cancer. CDK2 plays a different role in cell division from CDK 4 or 6 and is activated by a partner protein called cyclin E. Cyclin E is amplified in some tumors, which is believed to lead to tumor dependence on CDK2 for growth and survival. In HR+/HER2- breast cancer, the expression of cyclin E (with or without genomic amplification) is associated with resistance to CDK 4/6 inhibitors suggesting that CDK2 inhibition could prevent or overcome resistance to CDK 4/6 inhibitors in this setting.

The discovery of novel CDK inhibitors has historically been challenged by achieving the desired selectivity for the CDK of interest while avoiding activity against other CDKs. For CDK2, we set out to discover a selective compound that avoided inhibiting other critical CDKs, including CDK1. Conventionally, this would be accomplished with empirical medicinal chemistry, which has resulted in agents with sub-optimal selectivity profiles.

We applied the physics-based computational part of our Dynamo platform to model the interaction of CDK inhibitors with CDK2 and other CDK family members, allowing us to develop a predictive computational model to rationally design selective CDK2 inhibitors rather than engage in a long empiric medicinal chemistry campaign.