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Biography

John grew up in Derbyshire, attending Shirebrook Comprehensive through the '84 miners' strike and went to University as a first-generation scholar. He took a degree in chemistry with European studies (French) at Sussex, before embarking on a PhD in palladium chemistry in the Pfeffer lab (Strasbourg) and a postdoc, working on Josiphos chemistry, with Togni (ETH Zürich).

Returning to the UK, he was thrown into the daunting deep end of medicinal chemistry in small biotech and finally found his feet at the James Black Foundation where he ran a parallel synthesis group contributing towards preclinical candidate CCK2 and PTH-1 antagonists, after working on a Ph II (TRI50b) thrombin inhibitor at the Thrombosis Research institute.

He returned to academia, first at Greenwich then back to Sussex 14 years ago, obtaining his chair in Bioorganic ÉîÒ¹¸£Àû¹ú²ú¾«Æ· (2016), directing the Sussex Drug Discovery Centre for two years before stepping down to concentrate on writing grants and papers and directing medicinal chemistry.

His work is highly collaborative and varied and includes synthetic chemistry such as C–H activation, multicomponent chemistry and late stage functionalisation of medicinal chemistry relevant scaffolds, linkers and heterobifunctional molecules such as PROTACs. In medicinal chemistry, alongside Alan Fersht and Andreas Joerger (LMB, Cambridge) he has contributed to a better understanding of p53 mutant reactivators, which has served as a foundation for the advancement of Y220C activators in the clinic and, with Profs Fran Platt and Grant Churchill (Oxford) he has advanced knowledge of the mode of action of N-acetyl-leucine, a recently approved repurposed drug, for the treatment of the rare lysosomal storage disease, Niemann Pick C.

I've been blessed to be paid for my hobby and to work with amazing people, superb researchers in my group and collaborators all over the world to achieve this.

John Spencer

Q&A

Can you tell us more about your work?

Drug development suffers from many hurdles; high cost (several billion GBP per drug), long development times (usually, over a decade), high attrition rates (for every drug, thousands have failed!). New ways of making druglike molecules, by lowering costs, increasing productivity/efficiency are very much welcome.

We work on ways to speed up the synthesis of druglike molecules reducing energy, solvent use and waste while increasing efficiency and lowering costs. We can cut corners by testing lots of molecules made in very small amounts, most of which are discarded due to lack of biological activity. Those that pass the first test are then remade and retested.

Other research looks at using X-ray crystallography to better understand how drugs work on proteins, notably in cancer. Knowing how they attach to a protein enables us to better understand how they work, how to stop them working on other proteins, to reduce side effects, and how to improve them.

Who or what first sparked your interest in chemistry, and how has that interest evolved over time? 

Photography has always been a huge passion of mine and I used to have a black and white darkroom to develop photos when I was about 12 years old. I think this would be the first chance I had of measuring and mixing things, in fact carrying out chemistry!

My chemistry has certainly evolved. Never in a million years would I have seen myself doing medicinal chemistry but it was down to finding my first job after an ETH postdoc, at Xenova (Biotech), in the UK. I do not think I did that well. It was too much of a change in chemistry and very daunting but I slowly began to understand the whys and the hows. Now, it's a little easier but still a massive challenge.

What have been the biggest challenges that you have faced over the course of your time in science, and what have you learned from those experiences? 

Funding. The amount of work needed to write a grant application. Perhaps, only 10% of the application is the scientific justification. Also, the wait, as you risk being scooped by a competitor and the topic no longer being relevant! The inconsistency. I've written bulletproof proposals that missed out by one place in the ranking and far inferior others, where for example, I rushed it to meet a deadline, that were funded! One thing is sure: if you don’t write a proposal, you won't get it so it's the school of hard knocks... learn from your mistakes, take the feedback on the chin, write that stroppy email but don’t sent it, bin it, and put that frustration/anger in to writing a better proposal next time.

What impact would you say that your work is having on your field and/or the wider world? 

I think that a lot of our work on the Y220C mutant in p53 has been impactful as we were able to define a roadmap of the protein, show how to bind small molecules in the cavity and how to optimise them.

Now there are promising drugs in the clinic that use some of the ‘tricks’ we brought to the table and this is satisfying.

Are there any scientific developments, either recent or on the horizon, that you are excited about? 

Drugging the undruggable. New ways and successes in targeting e.g. KRAS, p53, the use of beyond rule of 5 (bRo5) drugs including macrocycles, hetero-bifunctionals and a better understanding of their properties. Obviously, advances in e.g. Cryo-EM, Xray crystallography, AI are all helping.

What does good research culture mean to you, and why does it matter? 

I love to see people showing humility and kindness, who acknowledge their team members, technical staff, everyone who has contributed to the group. Those who let first authors have a * on a paper when their contribution is deserving. Remember, one day we were all striving to do bigger, better things and no doubt someone gave you a helping hand. Be proud and supportive of those who want to be the next PI.

What is your favourite element and why? 

Palladium. It was my PhD, it is so useful in both academic and industrial research and you only have to think of Suzuki, Heck, Negishi, Buchwald-Hartwig, etc, to realise just how important Pd-catalysed reactions are.