BMOL Seminar Series: Dr. Chase Neumann

Seminar Details

Speaker: Dr. Chase Neumann, Associate Director of Oncology at Recursion Pharmaceuticals

Host: Dr. Greg Hampikian, Biological Sciences

Title: The Recursion OS links RBM39 to CDK12 and enables the identification and rapid optimization of novel RBM39 degraders

Abstract: AI-enabled drug discovery is a powerful approach for identifying novel drug targets and may accelerate the speed at which medicines for many diseases can be discovered. We built a Recursion Operating System (OS), an end-to-end suite of AI-enabled, active-learning modules that can accelerate drug discovery from target identification to in vivo proof of concept. We employed several AI-enabled modules, the PhenoMap, MatchMaker, and InVivomics to identify a novel biological relationship between RBM39 and CDK12, a previously proposed oncology target. We then identified RBM39 degraders and showed that they function to specifically phenocopy inhibition of CDK12 but not CDK13 (a close paralog to CDK12). We employed the MatchMaker module for in silico mechanism of action de-risking to ensure that RBM39 degraders had no predicted off-target cyclin-dependent kinase (CDK) activity. We then leveraged the PhenoMap to rapidly optimize the RBM39 initial hit compounds, improving their potency and overall PK/ADME properties. We showed that lead Compound 4 shows robust RBM39 degradation, single-agent antitumor activity in vitro and in vivo in representative ovarian cancer models and synergizes with PARP inhibitors. Finally, using our InVivomics module, we identified potential tolerability and liver toxicity signals that may not have otherwise been detected with more traditional body weight measurements. We demonstrate the power of the Recursion OS and our AI-enabled modules in accelerating drug discovery and integration of these modules will ultimately disrupt the entire process of drug discovery.

Big Takeaway: This is the first example of an omics approach being used to drive chemical optimization. Also one of the first AI-driven drug discovery program to transition to clinical development.

Publication Related to Talk: Coming Soon!