Drik Kessler, Boehringer Ingelheim
The Power of Biophysics to Tackle KRAS and Its “Undruggable” Fellows

Mutations in KRAS, p53, beta-Catenin and MYC, the so-called “Cancer Big 4”, are the main drivers in cancer. All these proteins mainly signal via protein-protein interactions (PPI) with no obvious druggable pockets but large and flat interacting surfaces. Identification of inhibitors that avoid the formation of those large contacts remains a big challenge.

Here we discuss how extended use of biophysics such as NMR, SPR, H/D exchange and protein X-ray crystallography helped to identify inhibitors for three very challenging PPI targets namely mutant KRAS, its guanine nucleotide exchange factor SOS1 and the transcriptional repressor BCL6. The identification of probe molecules for these targets will be presented in more detail highlighting the importance of biophysics for the validation and progression of the hits up to the final molecules.  In addition, we will show how these methods also helped to understand some related scientific curiosities on a more atomic level.

Dr Stacey Southall, Sosei Heptares
Cryo-EM in GPCR Structure Based Drug Discovery

Structure-Based Drug Discovery (SBDD) for GPCRs has been revolutionized by the wealth of new structural information that has become available in recent years, enhancing our understanding of their function and the mechanism of action of ligands. X-ray crystallography has been the method of choice for GPCR structure determination and has been routinely used at Sosei Heptares, driven by access to stabilised receptors (StaR®). Cryo-electron microscopy (cryo-EM) has now become established as a complementary approach to determine novel structures and drive SBDD. Indeed, since 2017, more structures of GPCRs in the active state coupled to heterotrimeric G proteins have been determined by cryo-EM than by X-ray crystallography.

We will present how Sosei Heptares has integrated cryo-EM to our SBDD workflow, including the role of proprietary mini G technology for understanding ligand-induced GPCR activation and as a tool for facilitating structure determination. Exploitation of cryo-EM is now providing additional opportunities to solve structures of GPCRs for which limited tool ligands are available, which we will exemplify with cryo-EM enabled GPCR SBDD case studies.

Cryo-EM has clearly improved accessibility of challenging receptors to SBDD. In addition to assisting hit and lead generation for these valuable targets, the understanding of novel modes of binding opens new opportunities for modulating receptor function in disease. The structural revolution for GPCRs is now revealing the mechanistic details of this diverse range of orthosteric, allosteric and biased modulators and should drive SBDD of new therapeutic agents.