Molecular gymnastics worth 10 billion dollars

Specific covalent inhibitors have long been of great interest to many people, despite the fact that irreversible inhibition has not really been on the very top of pharma companies’ wish lists until recently. I do find this somewhat ironic given the fact that a great many useful medications owe their efficiency to the covalent mode of action. We do not have to go very far for examples – take aspirin for starters…

Today I want to talk about epoxomycin, a molecule that has been associated with the name of Professor Crews (Yale). The company that emerged from this technology, Onyx, was recently bought by Amgen for 10+ billion dollars. Kyprolis is the name of their drug, which is a close cousin of epoxomycin. The difference between the two is just a couple of modifications to improve solubility and other drug-like properties. 10 billion is a lot of value for a fairly simple epoxy peptide, which means that there’s more that meets the eye. Indeed, epoxomycin (an irreversible inhibitor of proteasome 20S) displays a marvelous mechanism of action. The molecular gymnastics that take place during its interaction with the terminal threonine of proteasome 20S are shown below. Obviously, this is not your typical epoxide that reacts by a classic Sn2 mechanism with some active site nucleophile. If you look closely, the interaction has two distinct steps: hydroxyl of Thr1 attacking the carbonyl group followed by amine reacting with the epoxide ring. Thus, the specificity is defined by a multi-center engagement, something that I think is worth emulating in other contexts. Below is a link to the Crews’ seminal paper.

ppppp

http://pubs.acs.org/doi/abs/10.1021/ja993588m

One thought on “Molecular gymnastics worth 10 billion dollars

  1. Pingback: A mechanistic revision | amphoteros

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