Webinar: New Oncology Targets from Fragment Leads
This webinar will focus on a novel fragment-based drug discovery, the development of p53 activators, and the high-throughput exploration of crude reaction mixtures through automated chemistry and X-ray crystallography.
Online
Speaker: John Spencer, PhD
- Head of Medicinal Chemistry, Sussex Drug Discovery Center
- Scientific Advisory Member (grant committee) Prostate Cancer UK
Topics:
- A novel fragment-based drug discovery
- The development of p53 activators
- The high-throughput exploration of crude reaction mixtures through automated chemistry and X-ray crystallography
Description:
The p53 protein, often referred to as the "guardian of the genome," plays a critical role in regulating cell cycle, DNA repair, and apoptosis. Mutations or dysregulations in p53 are implicated in over half of all human cancers, making it a prime target for therapeutic intervention. Despite significant progress, developing effective p53 activators poses numerous challenges. As a nuclear transcription factor, p53 does not possess typical drug target features.
Fragment-Based Drug Discovery (FBDD) is a powerful approach in drug discovery that involves the identification of small chemical fragments binding to a target protein, which are then optimized into potent compounds. We recently developed a streamlined workflow integrating low-cost robotics and analytical techniques to rapidly gather structural data on binding sites (Grosjean et al). By using crystallographic fragment screens of the pleckstrin homology domain interacting protein (PHIP(2)), 1800 compounds were synthesized using an OpenTrons OT-1 liquid handler. The workflow included multi-step reactions, deconvolution of crude reaction mixtures with MScheck, and subsequent X-ray diffraction analysis. This efficient process identified 22 crystallographic hits, with one molecule showing notable binding affinity. This approach promises to significantly expedite the fragment-to-lead drug development process.