Abstract

Expanding the Scope of Fragment-Based Hit Identification: Targeting Novel Mechanisms in Cancer

Justin Bower, Head, The Beatson Institute for Cancer Research

Protein Protein Interactions (PPIs) play a central role in most regulatory processes and disease mechanisms and many are attractive drug discovery targets.  In the main, High Throughput Screening (HTS) approaches towards finding suitable hits and subsequently viable leads against many PPI targets have failed to deliver.  Employing additional, differentiated methods of unearthing hits against this class of target represents an exciting opportunity.  Fragment screening has developed considerably in recent years and has been embedded as an attractive hit-finding paradigm in many organisations resulting in the delivery of many high quality clinical candidates and Vemurafenib (Xelboraf), recently approved by the FDA to treat patients with metastatic melanoma, possessing the B-Raf V600E mutation. The target agnostic design of fragment libraries lends itself to screening against a range of potential targets and the gain in understanding of how PPIs exert their biological effects coupled with developments in structural biology, biophysical screening technologies and computational disciplines is increasingly bringing this class of target within the range of Fragment-Based Drug Design (FBDD). This talk will explore the potential of using fragment-based methods to unearth hits against PPIs, detailing a current approach towards inhibiting a PPI involved in invasion and metastasis. In addition, a rudimentary discussion on fragment library composition will be included along with suggestions of how future, more structurally diverse fragments which occupy different regions of chemical space to the vast majority of current fragment libraries can be designed and selected.