New combination treatments in RAS-targeted cancer therapies
It’s amazing to think it was only a decade ago when RAS was thought to be an “undruggable” target in the cancer research world. However, despite years of failures, its critical role as a driver of cancer had led some researchers to continue to strive to crack the problem. The Shokat team’s seminal publication in 2013 did just that.1
That 2013 discovery of the mutant RASG12C druggable pocket has inspired the next generation of researchers to innovate and relook at the RAS targeting problem. This has not only led to the approval in 2021 of the first RAS-targeted cancer therapy for Non-small cell lung cancer (NSCLC), Sotorasib, it has also reinvigorated the entire RAS drug discovery field which now boasts a plethora of alternative RAS targeting approaches. These range from research into the other major RAS mutations in cancer (eg. G12D) to a whole host of RAS signaling regulatory proteins. The potential for combination treatments in this area is significant.
We are now starting to see some of the medicinal chemistry research papers which describe the discovery of these alternative RAS targeting approaches. One of these was published this month in the Journal of Medicinal Chemistry; the discovery of clinical candidate MRTX0902 from Mirati Therapeutics which is an inhibitor of the SOS1:KRAS Protein–Protein Interaction.2
What is striking is that now the aspiration and belief in the field is unlocked, many of the classical medicinal chemistry strategies are effective against these targets. In the paper by Ketcham et al, they describe a rational medicinal chemistry design approach to the identification of their clinical candidate.
Design ideas are informed by structure-based computational chemistry to optimize potency and design in selectivity against EGFR. To optimize in vivo exposure they profile candidates in in vitro ADMET assays and design out aldehyde oxidase mediated metabolism by blocking the key site for metabolism. Some interesting disconnects between human and rodent metabolism are described. And finally, to address potential drug-drug interactions they design out CYP3A4 activity by lowering the global lipophilicity.
The result is a candidate which combines with their RASG12C clinical compound Adagrasib (MRTX849) in a pancreatic cancer model to effect tumor regression as a combination treatment.
It’s going to be interesting over the coming years to watch as more of the medicinal chemistry drug discovery disclosures make their way into the literature and we see the breadth of what is possible in the re-energized RAS field.
- Jonathan M. Ostrem, Ulf Peters, Martin L. Sos, James A. Wells & Kevan M. Shokat*, Nature volume 503, 548–551 (2013)
- John M. Ketcham*, Jacob Haling, Shilpi Khare, Vickie Bowcut, David M. Briere, Aaron C. Burns, Robin J. Gunn, Anthony Ivetac, Jon Kuehler, Svitlana Kulyk, Jade Laguer, J. David Lawson, Krystal Moya, Natalie Nguyen, Lisa Rahbaek, Barbara Saechao, Christopher R. Smith, Niranjan Sudhakar, Nicole C. Thomas, Laura Vegar, Darin Vanderpool, Xiaolun Wang, Larry Yan, Peter Olson, James G. Christensen, and Matthew A. Marx, J Med Chem, asap https://doi.org/10.1021/acs.jmedchem.2c00741
Further reading