For students of anti-cancer drug development and history there’s a really nice review paper just published on some of the lessons learned from targeting the RTK/RAS/MAPK pathway, including KRAS, from the lens of structural biology.
There are plenty of examples shared using crystallography, as well as some important highlights along the way. They also mention the SHP2 molecular glues, which launched a new era in this niche with a flurry of companies and novel compounds rushing to evaluate their sparkly new SHP2 inhibitors in various dose escalation and expansion trials.
We’ve been following this niche since NIBR scientists reported important preclinical results with their original lead agent SHP099, an allosteric inhibitor which changed how many looked at phosphatases – finally it was a druggable target!
Fast forward five years and this weekend we heard the results from the improved clinical stage compound, TNO155, in an initial clinical readout from Novartis coming on top of the early data from Revolution Medicines at AACR with their SHP2 inhibitor, RMC–4630.
What did we learn and where are the company going with their approach?
Following presentation on the dose escalation cohort at ASCO over the weekend we received a bunch of reader questions and had some of our own too, so some expert commentary is included from the sponsor of the trial, Novartis.