1. Discovery of GSK251: A Highly Potent, Highly Selective, Orally Bioavailable Inhibitor of PI3Kδ with a Novel Binding Mode
David N Mallett, James Rowedder, Michael D Goldsmith, Niall A Anderson, Sebastien Campos, Nick Barton, Andrew Sharpe, J Nicole Hamblin, Sorif Uddin, Maire A Convery, Daniel A Thomas, Vipulkumar K Patel, Jana Krause, Douglas W Thomson, Augustin Amour, Edith M Hessel, Christopher D Edwards, Grant A McGonagle, Kenneth Down, Cole Clissold, Srividya Sriskantharajah, Birgit Duempelfeld, Paul Rowland, Edward P Cannons, Kevin Doyle, John J Coward J Med Chem . 2021 Sep 23;64(18):13780-13792. doi: 10.1021/acs.jmedchem.1c01102.
Optimization of a previously reported lead series of PI3Kδ inhibitors with a novel binding mode led to the identification of a clinical candidate compound31(GSK251). Removal of an embedded Ames-positive heteroaromatic amine by reversing a sulfonamide followed by locating an interaction with Trp760 led to a highly selective compound9. Further optimization to avoid glutathione trapping, to enhance potency and selectivity, and to optimize an oral pharmacokinetic profile led to the discovery of compound31(GSK215) that had a low predicted daily dose (45 mg, b.i.d) and a rat toxicity profile suitable for further development.
2. Discovery and Characterisation of Highly Cooperative FAK-Degrading PROTACs
John P Evans, Paul Scott-Stevens, John D Harling, Joao Nunes, Markus A Queisser, Antonia J Lewis, Andrew B Benowitz, Chun-Wa Chung, Karol Buda, Peter Stacey, Adam Flinders, Christopher J Tame, Han Dai, Gillian F Watt, Robert P Law, Diana Klimaszewska, Marcus Bantscheff, Marcel Muelbaier, Nico Zinn Angew Chem Int Ed Engl . 2021 Oct 18;60(43):23327-23334. doi: 10.1002/anie.202109237.
Focal adhesion kinase (FAK) is a key mediator of tumour progression and metastasis. To date, clinical trials of FAK inhibitors have reported disappointing efficacy for oncology indications. We report the design and characterisation of GSK215, a potent, selective, FAK-degrading Proteolysis Targeting Chimera (PROTAC) based on a binder for the VHL E3 ligase and the known FAK inhibitor VS-4718. X-ray crystallography revealed the molecular basis of the highly cooperative FAK-GSK215-VHL ternary complex, and GSK215 showed differentiated in-vitro pharmacology compared to VS-4718. In mice, a single dose of GSK215 induced rapid and prolonged FAK degradation, giving a long-lasting effect on FAK levels (≈96 h) and a marked PK/PD disconnect. This tool PROTAC molecule is expected to be useful for the study of FAK-degradation biology in vivo, and our results indicate that FAK degradation may be a differentiated clinical strategy versus FAK inhibition for the treatment of cancer.
