17 Sep Modifying Approved Drug Offers New Pathway to Treat Resistant Cancers
MedicalResearch.com Interview with:
Dr. Arvin C. Dar, PhD
Departments of Oncological Sciences
& Pharmacological Sciences
Tisch Cancer Institute
Icahn School of Medicine at Mount Sinai
Mount Sinai Center for Therapeutic Discovery
MedicalResearch.com: What is the background for this study?
Response: We were interested in better understanding the mechanism of action for the drug trametinib. We wanted to understand how the drug actually works – even though its clinically approved, the drug was a ‘serendipitous discovery’ and originally found through phenotypic screens.
MedicalResearch.com: What are the main findings? What types of cancers might this new analog be effective against?
Response: We were able to solve the first co-crystal structures of trametinib, and found – somewhat unexpectedly – that the drug binds at the interface of a complex between MEK and KSR. We used a number of approaches to show that the binding of the drug at the interface of this complex is what makes trametinib special, and a promising therapeutic lead.
However, while promising trametinib is limited due to poor efficacy and also adaptive resistance mechanisms. Trametiglue is different from trametinib because it was designed to enhance interface binding of MEK co-complexes. As a result, the drug is more efficacious and less susceptible to resistance.
Trametiglue could be beneficial in a number of settings, but our data thus far suggests it could be particularly effective in KRAS mutant cancers, such as pancreatic, lung, colon, and melanoma.
MedicalResearch.com: What should readers take away from your report?
Response: That the functional co-receptor and mechanism of action for a clinically approved drug was not fully understood. However, with this understanding my lab was able to make improved analogs in a rational structure-based manner. Trametiglue may open opportunities for further drug development using similar approaches/strategies.
MedicalResearch.com: What recommendations do you have for future research as a result of this work?
Response: There are a few examples where a drug was approved for clinical use before its mechanism of action or targets were fully understood. Examples are rapamycin and thalidomide. In these cases, understanding the targets opened a lot of new biological discoveries and also drug develop opportunities. There is a chance that the same could happen here.
Any disclosures? Mount Sinai has filed a patent on this work.
Khan, Z.M., Real, A.M., Marsiglia, W.M. et al. Structural basis for the action of the drug trametinib at KSR-bound MEK. Nature (2020). https://doi.org/10.1038/s41586-020-2760-4
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