John Taylor

With Social Mobility Day just around the corner here in the U.K., this fantastic article explores the impact of being a 1st Gen science student: pubs.rsc.org/en/content/a...

It destroys some of the myths we tell ourselves about STEM being a meritocracy, and is a timely call to action

The final version of our RAS inhibitor manuscript has now been accepted as a Featured Article in J Med Chem; thanks to the reviewers and editors for their valuable input

pubs.acs.org/doi/10.1021/...
🧪⚗️ #ChemSky

🔜
#KRas #JMedChem

COMING SOON! Sneak preview of the selection of people we're showcasing this month 🧪

Bluesky Chem Starter Packs

Did some tidying up of the links for chemistry related starter packs, arranged loosely by subject area, and added who maintains the list so you know who to speak with if you'd like to be added!

tinyurl.com/ChemSkyStart...

#ChemSky #Chemistry #Chemists #StarterPacks 🧪

📯 Chemical Biology starter pack No.1: now with 📯 #chembio Feed 📯 (also gets #chemicalbiology)

#ChemBio feed: bsky.app/profile/did:...

Pack covers 150 groups posting primary research in chemical biology:
go.bsky.app/KLrTWoj

📬 Please Repost !📬

#realtimechem #FluorescenceFriday #chemsky #scisky

Women in chemistry starter pack here: go.bsky.app/LjumNEg
#ChemSky
please repost :D

#ChemSky #realtimechem #FluorescenceFriday

Applications are open for the James McCune Smith (JMS) Scholarships here
@uofglasgow.bsky.social. which fund Black UK students to undertake PhD research in Glasgow in any field. They provide an enhanced experience and are very well-supported. www.gla.ac.uk/scholarships.... Please share this widely

Any feedback on the pre-print or questions around the work, let me know!

It was also a true model of collaborative science, with hundreds of scientists contributing to the wider project over the years, including collaborators at the NCI and Novartis. I was privileged to co-lead for a period at the end, but very much stood on the shoulders of giants here!

Hopefully, however, it still serves as informative for those working on RAS, particularly the new structural data and SAR around active & inactive RAS. There’s also learning on the power of fragment-based, structurally-enabled hit-finding for challenging targets, and how best to optimise them.

Nevertheless there are real challenges around these compounds. We were able to show cellular activity, but weaker binding to active RAS and their properties meant progressing this series was hard. We looked to address the high TPSA and issues around the phenols, but that’s a story for another day.

From a structural interest point of view, it is notable that these compounds bind proximal to the nucleotide binding site, forming an interaction with the Mg ion present here.

Cartoon showing a molecule with an amino piperidine group pointing towards the nucleotide binding site of KRAS

We discovered a number of analogues which formed a bidentate interaction with Asp38, pushing Switch I into a completely new orientation with Glu37 out of the pocket! Interestingly, some of these compounds seem to show a slight preference for binding to the active forms of RAS c.f. inactive.

Cartoon showing a molecule with an amino-pyrrolidine pushing in between Switch I & Switch II of KRAS

By swapping out the phenol for an amino-pyridine, we were able to find compounds which did just that. Despite the affinity towards the inactive forms of RAS dropping off with this series, they maintained their single digit micromolar affinity to the active forms, making them roughly equipotent.

Cartoon showing a molecule bound in the Switch I/II pocket of KRAS, with an exit vector on the interface of these switches

As well as the strategy of designing compounds that fit more readily into the constraints of this smaller pocket in the active form, we considered an other approach. Can we push deeper into this site, and pick up interactions with a different residue, recovering the affinity towards the active form?

Cartoon showing 2 molecules bound in the Switch I/II pocket of KRAS; the left hand one interacts with Glu37, whilst the right hand one clashes

We think this may be due to the preferred orientation of the Glu37 residue in this active form – despite being distal to the nucleotide binding site, in a number of our ligand-free structures, it seems happier moving into the area occupied by this series:

This worked! It also delivered molecules with single-digit nanomolar binding affinity to the GDP-loaded, inactive form of a range of RAS mutants and isoforms. However, we experienced a big drop-off of binding affinity to active RAS proteins, and this was borne out in the activity of our compounds.

Cartoon showing two molecules bound in the Switch I/II pocket of KRAS, one with two ethyl groups proximal to each other, and one where they have been tethered in a macrocycle

The big step forward came when we solved the crystal structure of compound A below, which suggested that forming a macrocycle between the amide nitrogen and the one on the benzothiazole ring could constrain our molecules in the bioactive conformation:

Cartoon showing two molecules bound in the Switch I/II pocket of KRAS, making interactions with Asp54, Gln70 & Glu37

Using structure-guided design principles, we were able to optimise these hits, which were shown to bind in the Switch I/II pocket (similar to compounds from the Fesik group, and Boehringer’s BI-2852)

Table showing 4 chemical fragments, alongside their Kd for KRASG12D.GDP as measured by NMR (370 - 700 micromolar)

One of the initial aims of our Programme was to establish a fragment-based platform to find hit matter for challenging targets previously considered “undruggable”, such as GTP-ases. From this, we discovered a number of novel, structurally-enabled fragment hits, weakly bound to KRAS:

Whilst this was written and published under the current Cancer Research Horizons affiliation of our group, the genesis of this work goes back 15 or so years to our previous incarnation, when we were the CRUK Beatson Institute (now CRUK Scotland Institute) Drug Discovery Programme.

Reversible Small Molecule pan-Ras Inhibitors Display Tunable Affinity for the Active and Inactive forms of Ras. Activating mutations of Ras are one of the most prevalent drivers of cancer and are often associated with poor clinical outcomes. Despite FDA approval for two irreversible inhibitors that target the i...

Hi #Chemsky, time for a quick thread on our latest pre-print: “Reversible Small Molecule pan-Ras Inhibitors Display Tunable Affinity for the Active and Inactive forms of Ras” ⚗️🧪

chemrxiv.org/engage/chemr...

YouTube video by Chemistry World Empowering voices – Advancing social mobility in the chemical sciences

Missed the @roysocchem.bsky.social Social Mobility in the chemical sciences Webinar held on #SocialMobilityDay ?

Re-watch @chemistryworld.bsky.social webinar with inspiring & insightful stories from those working in socioeconomic inclusion #RSCSocioeconomicInclusion

www.youtube.com/watch?v=pEzt...

Reversible Small Molecule pan-Ras Inhibitors Display Tunable Affinity for the Active and Inactive forms of Ras. Activating mutations of Ras are one of the most prevalent drivers of cancer and are often associated with poor clinical outcomes. Despite FDA approval for two irreversible inhibitors that target the i...

Hi, could I be added to the Science feed please? I’m a medicinal chemist working in drug discovery- here’s the latest preprint from our group: chemrxiv.org/engage/chemr...

Sign the Petition Stop University of Reading from closing the Department of Chemistry

Calling #ChemSky, activation time is now! ⚗️🧪

My old Chemistry department at the University of Reading is being forced to close (*). There are lots of students worried about the validity of their degrees and lots of staff worried about their jobs. Please sign!
www.change.org/p/stop-unive...

When the exotherm did finally kick in and melt all of the ice simultaneously, there was not much left to do, except pull the fumehood sash down and wait for the show to stop before cleaning up

Quenched a reaction containing POCl3 by adding ice to the reaction flask. When nothing much happened, I added more ice…

Starting afresh here, hoping to find that great community of science and discussion that “the other place” once had.
I’m a medicinal chemist based in Glasgow, Scotland and am looking forward to sharing chemistry and drug discovery thoughts on here 🧪