Headshot of researcher wearing glasses
Ben Shen, The Scripps Research Institute (Courtesy of B. Shen)

This is our conversation with Professor Ben Shen, from The Scripps Research Institute (TSRI) in Jupiter, Florida. Ben and Alison and I talk about enediynes and their use in medicine, how Ben got fascinated with natural products by working on terpene chemistry, TSRI’s acquisition of the Pfizer strain collection, and our collaborations to sequence that collection, mine genomes, and develop new technology to access natural products. 

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Show Notes

As promised in the intro to Episode 7, here is some additional info about “enediynes”, one of the most toxic classes of natural products known!

The name comes from their core chemical structure: one “ene” – that’s two carbons attached by a double bond – and to “ynes” – two more pairs of carbons attached by triple bonds, each one attached to one end of the double bonded carbons. This is hard to say coherently, and harder to type, so here’s a drawing.

On its own, this is a really unstable configuration of carbons, and, instead, these six carbon really want to rearrange into a six-membered aromatic ring. When they do that, they end up creating a “di-radical” which can wreak reactive havoc on almost any other molecule. However, in the natural product versions of enediyne molecules, there’s a whole bunch of other atoms that can either stabilize the enediyne, and/or provide the chemistry needed to direct this unstable warhead to its target.

As we discuss in the podcast, enediynes are often used as the “payload” on an antibody-drug conjugate, or “ADC”. The enediynes that we find in nature weren’t evolved for the purpose of killing human cancer. But, some are very toxic and can be used that way – the main side problem being that they also kill regular cells too! So, scientists figured out that if you take an antibody that can recognize and bind to cancer cells, and then you attach a toxic molecule – like a natural product enediyne – to it, then the antibody will bring the toxic molecule straight to the cancer cells and the toxin can kill it. Teamwork!

 

If you’re somewhat knowledgeable in natural products or biosynthetic chemistry and want to dive deep on the topic, or just want to take a look at several natural product enediyne structures, Ben’s 2015 paper on genome mining for enediynes is one of my favorites.