Please can you give a brief introduction to MYC and the role it plays in many cancers?
MYC is an oncogenic member of the basic helix-loop-helix-leucine zipper transcription factor family.
In its monomeric form, MYC’s tertiary structure is intrinsically disordered and the protein is transcriptionally inactive. However, upon dimerizing with its relative MYC-associated factor X (MAX), an obligatory event that is required for all MYCs known biological activities.
Unlike MYC, MAX forms homodimers, as well as heterodimers with other family members that include MAD proteins and MNT. These dimers retain the ability to bind E-boxes but repress transcription by competing with MYC-MAX heterodimers, thus providing one means by which MYC’s transcriptional activity is kept in check.
MYC is important in the transcription of a myriad of genes involved in roles that include cell proliferation, apoptosis, differentiation and metabolism. The deregulation of MYC is associated with most human cancers, including but not limited to, leukaemias, and lymphomas as well as cancers of the breast, pancreas, lung and colon.
Why had MYC previously been thought to be “undruggable”?
Two reasons:
(1) Given its central role in many key cellular processes, there was concern that successful design of nontoxic inhibitors could prove especially challenging.
(2) The MYC-MAX dimer interface is what is termed a “protein- protein interaction”; this heterodimer interface contains a surface of over 3,200 angstroms, which needs to be accounted for when designing a small molecule inhibitor that will disrupt MYC-MAX binding.
How important is determining the structure of disease-related molecules when designing drugs?
It is important but not rate limiting there are other biophysical means to characterize protein targets, but clearly having a well defined structure can readily help in the drug design process.
Why does the structure of MYC constantly shift at body temperature?
MYC is basically a disordered protein. As the temperature increases it'll become more disordered and have more movement to it.
How did you overcome the problem of the constantly changing structure of MYC?
That's a good question and I’m afraid we don’t know exactly how the molecules target MYC.
We're not completely sure if the molecule binds MYC directly or if it disrupts MYC-MAX.
We know it works but I can't really state exactly how it recognizes MYC, which does not take on a fully organized structure in its monomeric form.
My guess is that it's binding in such a fashion that it won't allow MYC -MAX to come together. You've got to imagine that MYC-MAX are in constant equilibrium. They're coming off, coming on, coming off, coming on.
I think what the small molecule does is it traps MYC at some point and doesn't allow them to come back together.
How many molecules did you test before you found one that disrupted MYC’s interactions with proteins involved in cell proliferation?
When we did this originally with Pfizer and another group that had a their own in house library; I think they tested millions of structures. I only had a small library of about 220. But this library was specifically made to disrupt protein-protein interactions. So it's not always that bigger is better.
I originally designed this almost 15 years ago and I was very focused on a specific scaffold. I've always been of the opinion that if you can't find what you need within a few hundred then that scaffold or core structure that you're investigating is probably not going to be of value to the target you're trying to selectively focus upon.
What further research is needed to understand how KJ-Pyr-9 interacts with MYC?
We've been very interested in exactly how KJ-Pyr-9 binds and how it disrupts MYC: that's one of the pieces of the puzzle that we'd like to further understand.
We're also making some other molecules to see if we can improve upon its overall pharmacokinetic and pharmacodynamic properties that it can have in terms of moving it forward into more clinical settings.
What impact do you think this research will have?
I think it opens up the door where people have looked at trying to target this interaction (MYC-MAX) for many years. Countless groups have dropped this research and many pharmaceutical companies said it's probably not doable.
I think what this shows is that it is doable and this research is probably going to get people back into the game again. Hopefully we can use this to leverage other molecules for targeting a myriad of different types of cancer.
Where can readers find more information?
More information can be found in the recent paper published in the journal Proceedings of the National Academy of Sciences
About Professor Kim Janda
Scripps Research Institute Professor Kim D. Janda is considered one of the first scientists to merge chemical and biological approaches into a cohesive research program. Combing the principles of medicinal chemistry with modern molecular biology, immunology, and neuropharmacology has enabled Janda and his group to create both synthetic/natural molecules and processes with biological, chemical, and physical properties. This has included potential new approaches to problems including combinatorial chemical libraries, antibody catalysis, biodefense threat agents, bacterial communication/biofilms/infection, obesity, drug addiction, diabetes, and parasitic diseases.
Currently the Ely R. Callaway, Jr. Chair in the Departments of Chemistry and Immunology & Microbial Science at Scripps Research, Janda is also director of the Worm Institute of Research and Medicine (WIRM) and a Skaggs Scholar in Skaggs Institute of Chemical Biology at Scripps Research. He holds a BS degree from the University of South Florida in Clinical Chemistry and a doctoral degree from the University of Arizona (advisor Robert B. Bates) in natural product total synthesis.
Over a career of almost 25 years, Janda has published more than 400 original publications in refereed journals and founded the biotechnological companies CombiChem, Drug Abuse Sciences, and AIPartia. He is associate editor of Bioorganic & Medicinal Chemistry and PloS ONE and serves, or has served on, numerous journals including Journal of Combinatorial Chemistry, Chemical Reviews, Journal of Medicinal Chemistry, The Botulinum Journal, Bioorganic & Medicinal Chemistry, and Bioorganic and Medicinal Chemistry Letters.
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