Proteasome Inhibitors, Refined

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Proteasome Inhibitors, Refined

The Proteasome is quite the structure. It is the shredding unit of the cell, where no-longer-needed proteins go to be ripped down to their components for recycling, and it’s become a more and more important part of drug discovery over the years. For one thing, all this fashionable targeted protein degradation work is about sending designated proteins off for destruction at will and before their time. But even before that, the opposite process – proteasome inhibition – had made an impact.

That’s because there are cancer cells that (because of their higher metabolism, greater production of various proteins, etc.) are more sensitive to problems with proteasomal function, and will die more quickly when the waste-disposal service is interrupted. The first compound on the market to do this was Velcade (bortezomib), which was approved in 2003 for multiple myeloma. It came out of a small company called Myogenics, then was developed further at Millennium, and was also notable for having a boronic acid head group. Those had been known as enzyme inhibitors for a long time, but were thought by many to be unfit to get all the way through clinical trials (after a number of failed development projects during the 1980s and onward).

Another inhibitor, Kyprolis (carfilzomib) was approved in 2012, and that one has an epoxide as the warhead, which is also a bit unusual (it had its origins in a natural product). In 2015 came Ninlaro (ixazomib), another boronic acid. Still in clinical trials are the epoxide oprozomib, the boronic acid delanzomib, and the unusual beta-lactone marizomib (also known as the marine natural product Salinosporamide A). That last one is notable for having gone from “here’s a new natural product” to “here’s an IND application” in what may be record time. Now, this list might be seen as an egregious example of “me-too” drugs gone crazy. How, you wonder, did the world end up with so many proteasome inhibitors, especially since several of them look so similar to others in the same class?