Science & Platforms
FMC-376 a dual inhibitor of states of KRASG12C is broadly active in PDX models of resistance
Yan Wang, Richard M. Neve, Jocelyn Staunton, Kevin R. Webster
Scientific Approach
The Science Behind the Story
Nearly two decades have passed since the sequencing of the human genome, which has greatly facilitated our understanding of cellular mechanisms of action, systems biology and – importantly – the identification and validation of disease targets. Yet many of these targets are neglected; usually because they fall outside what has been historically considered druggable. This greatly limits the number of targets implicated in disease that are accessible to therapeutic intervention.
Enabling transformative access to therapeutic targets
In order for a drug to be effective against a protein, it needs first to bind to it. Until now, approximately 90% of human proteins have not been effectively targeted by small-molecule drugs because there are no known binding sites on the surface of the protein and existing chemical libraries have failed to yield leads. Many exciting, well validated therapeutic targets do not contain classical binding sites and thus demand innovative approaches. Frontier has a unique methodology for pushing the boundaries of this scientific frontier.
Less than 10% of human proteins are accessible to small molecules
With The FrontierTM Platform we now have access to over 90% of human proteins
The FrontierTM Platform is powered by chemoproteomics, covalent chemistry, and machine learning
Unlocking access to formerly undruggable cancer drivers
Frontier is developing precision medicines against important disease-causing proteins that the biopharma industry has not been able to drug with standard pharmaceutical interventions. We have established The FrontierTM Platform that leverages groundbreaking scientific approaches in chemoproteomics, covalent drug discovery, and machine learning to uncover and pharmacologically target pockets within disordered regions and cryptic binding sites on these proteins, making them accessible to therapeutic intervention by small-molecule drugs.
Bailey, Ding et al. 2018 Cell 173,389
Tackling important disease drivers
Frontier’s initial focus is on the development of cancer therapeutics. Decades of research have identified critical cancer-causing proteins that to-date have not been successfully drugged. The need for truly novel classes of anti-cancer therapies remains high. There were an estimated 19.3 million new cancer cases and almost 10 million cancer deaths worldwide in 2020 (doi: 10.3322/caac.21660). Frontier’s pipeline tackles the most important disease drivers and provide patients with novel, more effective precision cancer therapeutics.
PUBLICATIONS
The clinical dual KRASG12C inhibitor FMC-376 has demonstrated potential as both a monotherapy and in combination for the treatment of patients with KRASG12C mutation positive NSCLC
Yan Wang, Allison Roberts, Philamer Calses, Richard M. Neve, Jocelyn Staunton, Kevin R. Webster
Combining Chemoproteomics with Machine Learning Identifies Functional Covalent Fragments for Hard-to-Drug Cancer Drivers
2023 American Association for Cancer Research Annual Meeting (Abstract 1142)