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Highlights from the 20th Joint SCI/RSC Medicinal Chemistry Symposium, Cambridge, UK

In my humble opinion, this meeting is one of the best medicinal chemistry conferences to attend and as usual the scientific content, on the whole, did not disappoint. There were many insightful talks and detailed ‘walk-throughs’ of the chemistry optimization paths for numerous biological targets. Thirty-one talks in all, and twenty-six flash poster presentations, was certainly more than enough science to get your teeth into and far too many to mention all here.

GPCRs and proteases

Remarkably, and despite the recent explosion in diversity of biological targets currently being pursued by discovery organizations, about thirty percent of the talks were on one of the oldest drug target classes I can think of ‘GPCRs and proteases’. Both Johnson & Johnson and Idorsia disclosed structures of their selective Orexin 1 antagonist programme candidates (table1a). The former, interestingly, containing methylene deuteration to counter an adverse metabolism event.

Table 1a: GPCR examples
JNJ: JNJ-61393215 Idorsia: ACT-539313 Binding hypotheses
JNJ: JNJ-61393215

Idorsia: ACT-539313

Orexin ligands modeled into the orexin receptor (PDB: 4ZJC) using Flare™
OX1 antagonist for anxiety OX1 antagonist for anxiety Both orexin ligands were modeled into the orexin receptor (PDB: 4ZJC) using Flare

Several other GPCR examples were described, including another talk from Idorsia and talks from Roche and Eli Lilly.

It is usually the end point molecule which sticks in the mind but far more important, yet often overlooked, are the lessons learned during the journey. I have tried to include at least some of the starting points in the Tables 1-4.

Table 1b

Starting hit

Starting hit

Starting hit for Cenerimod

Starting hit for LY3154207

Idorsia: Cenerimod

Eli Lilly: LY3154207 Roche: RG7314: Balovaptan
Idorsia: Cenerimod Eli Lilly: LY3154207 Roche: RG7314: Balovaptan
S1P1R selective modulator for autoimmune disease D1 positive allosteric modulator for Parkinson’s disease and dementia V1A antagonist for autism

Three widely differing protease targets were tackled by Genentech, Novartis and Almac showing diverse approaches to this challenging target family (table 2). Almac’s innovative ubiquitin specific protease inhibitor platform finally yielded structural biology to top off their hard won USP7 inhibitor story.

Table 2: Protease inhibitor examples
Starting hit
Starting hit protease inhibitor
Novartis Almac Genentech: G0775

Novartis Malt1 inhibitors for autoimmune disease

Almac USP7 inhibitor PDB: 5N9T for oncology

Genentech: G0775 LepB peptidase inhibitors for gram-negative antibiotics
Malt1 inhibitors for autoimmune disease

USP7 inhibitor PDB: 5N9T

for oncology

LepB peptidase inhibitors

for gram-negative antibiotics

Enzymes

Talks from Rodin, Bayer and Imperial described two relatively old enzyme targets ‘HDACs and DHODH’ and a very new one ‘NMT’. The former talks focused on attaining selectivity and or good PK properties as the value differentiator.

Ed Tate’s talk from Imperial, shed some light on a poorly understood field ‘post translational modification’. In this case, the importance of NMT mediated myristoylation on the activation of essential proteins needed for the malarial parasite life cycle was elegantly exploited.

Table 3: Enzymes
Rodin: RDN-929 Imperial Bayer: BAY 2402234
Rodin: RDN-929 Rodin: RDN-929 Bayer: BAY 2402234
HDAC-CoREST inhibitor for synaptopathies NMT inhibitor anti-malarial DHODH inhibitor for oncology

Immune sensing and RNA recognition pathways

Treading into completely new areas, talks by Gilead and GSK covered immune sensing or RNA recognition pathways which contain ‘hot’ target proteins important for immuno-oncology and anti-viral therapies.

Table 4: Other receptors
Gilead: GS-9688 GSK: ABZI
Gilead: GS-9688 GSK: ABZI
TLR8 agonist for Hepatitis B

Synthetic Sting agonist PDB: 6DXL

for immuno-oncology

Probing the nature of drug-space post Lipinski

A final take home message for me was a great pair of overviews delivered by Rob Young (Blue Burgundy) and Mike Shultz (Novartis) representing a return to probing the nature of drug-space post Lipinski. It turns out that drug molecules, by nearly every metric, are bigger than they were 20 years ago. The exception is H-bond count.

Sadly, I have to concur on a personal level with Robs parallel of drug properties with the middle-aged male waistline, but more so to his working talk title: Rules are for the obedience of fools and guidance of the wise.

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