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JohnTaylor boosted
Chembellenie

Some nice work from Ethan Toriki, James Papatzimas, Daniel Nomura and coauthors on bioRxiv biorxiv.org/content/10.1101/20

I think this is the first example in the “glue degraders” field where someone found a “degrading handle” that could be attached to multiple different inhibitors to give degradation of different proteins. A nice step forward in the rational design of molecular glue degraders!

#TPD #MedicinalChemistry #degraders

Rational Chemical Design of Molecular Glue Degraders

Targeted protein degradation with molecular glue degraders has arisen as a powerful therapeutic modality for eliminating classically undruggable disease-causing proteins through proteasome-mediated degradation. However, we currently lack rational chemical design principles for converting protein-targeting ligands into molecular glue degraders. To overcome this challenge, we sought to identify a transposable chemical handle that would convert protein-targeting ligands into molecular degraders of their corresponding targets. Using the CDK4/6 inhibitor Ribociclib as a prototype, we identified a covalent handle that, when appended to the exit vector of Ribociclib, induced the proteasome-mediated degradation of CDK4 in cancer cells. Covalent chemoproteomic profiling of this CDK4 degrader revealed covalent interactions with cysteine 32 of the RING family E3 ubiquitin ligase RNF126. Structural modification of our initial covalent scaffold led to an improved CDK4 degrader with the development of a but-2-ene, 1,4-dione ( “ fumarate ” ) handle that showed improved interactions with RNF126. Thereafter, we worked to identify the minimum covalent motif required for interaction with RNF126, which we then transplanted onto chemically related and un-related protein-targeting ligands. This strategy successfully produced molecules which induced the degradation of several proteins across diverse protein classes, including BRD4, BCR-ABL and c-ABL, PDE5, AR and AR-V7, BTK, LRRK2, and SMARCA2. Our study undercovers a design strategy for converting protein-targeting ligands into covalent molecular glue degraders. ### Competing Interest Statement JAT, JMK, DD, MJH, MS, and LM are employees of Novartis Institutes for BioMedical Research. This study was funded by the Novartis Institutes for BioMedical Research and the Novartis-Berkeley Translational Chemical Biology Institute. DKN is a co-founder, shareholder, and scientific advisory board member for Frontier Medicines and Vicinitas Therapeutics. DKN is a member of the board of directors for Vicinitas Therapeutics. DKN is also on the scientific advisory board of The Mark Foundation for Cancer Research, Photys Therapeutics, and Apertor Pharmaceuticals, and is a consultant for MPM Capital and Droia Ventures.

www.biorxiv.org
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JohnTaylor boosted
Kamyar Hadian

A bit late, but here is my #introduction. I am biologist and a Group Leader @HelmholtzMunich. We study #CellDeath mechanisms and translate these findings into future drugs using #ChemicalBiology and #DrugDiscovery approaches. We are particularly interested in deciphering the cellular mechanisms controlling #Ferroptosis and characterizing regulators of #Ubiquitin Signaling in #CellDeath pathways. In addition, my lab operates the Compound Screening Platform with strong expertise in #HTS and #HCS.

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JohnTaylor boosted
Clemens Isert

Mentioning this here as well: New(ish) review. Many geometric #deeplearning methods use the 3D structure of macromolecules to predict properties that are relevant for #drugdesign.
Preprint: arxiv.org/abs/2210.11250
Work with @atzkenneth & Gisbert Schneider.
#compchem #machinelearning #drugdiscovery (1/4)

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JohnTaylor boosted
Yael David Lab

🎉Happy to see our new ChemBioChem work led by Devin Ray out exactly on time for our traditional graduation 1:1 dinner…
Proud of you Devin 😍 & good luck in going back to the clinic!
Stay tuned for the cover🤩
@Ruben

onlinelibrary.wiley.com/doi/10

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JohnTaylor boosted
Jonas Verhellen

Now that I have the opportunity, let me our quality-diversity algorithm to Mastadon. It's based on @janhjensen 's generative algorithm. We avoid stagnation issues, and illuminates opportunities across chemical space, and outperforms approaches!

Code: github.com/Jonas-Verhellen/Arg

Paper: pubs.rsc.org/en/content/articl

GIF
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JohnTaylor boosted
Henry Ngo

#introduction time now that I'm ready to start trying mastodon out!

I currently work as a data scientist in the population health realm. Our team supports public health decisions. Previously, I was a research astronomer; my PhD work was on #exoplanets.

I'm a dad to 3 kids, 5 and under, and we live on unceded Snuneymuxw territories.

On Mastodon, I hope to stay in touch with astronomers and meet other cool folks! I'll probably toot about parenting and science.

#astrodon #astronomy

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JohnTaylor boosted
Caroline Lynn Kamerlin

Are you a prospective PhD student excited about Quantitative Biology? If so, Georgia Tech has an amazing interdisciplinary PhD program for you (QBios). Apply to join us by December 1st!

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JohnTaylor boosted
Stuart Cantrill

Hi #ChemiVerse

I might come to regret this, but I've seen some journalists compiling lists of people on here & I thought it might be useful in the early days here to do something similar for the chemistry community (& those who interact with the chemistry community – you can define that quite liberally).

So, here is a Google Form that you can fill in if you wish: forms.gle/gF9MLUGMWs23EFix6

And it feeds into this Google Sheet: docs.google.com/spreadsheets/d

(The form does not collect e-mail addresses)

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JohnTaylor

Really nice review just published on the use of covalently-bound fragments in by some current and former colleagues

mdpi.com/1424-8247/15/11/1366

Reactivity of Covalent Fragments and Their Role in Fragment Based Drug Discovery

Fragment based drug discovery has long been used for the identification of new ligands and interest in targeted covalent inhibitors has continued to grow in recent years, with high profile drugs such as osimertinib and sotorasib gaining FDA approval. It is therefore unsurprising that covalent fragment-based approaches have become popular and have recently led to the identification of novel targets and binding sites, as well as ligands for targets previously thought to be ‘undruggable’. Understanding the properties of such covalent fragments is important, and characterizing and/or predicting reactivity can be highly useful. This review aims to discuss the requirements for an electrophilic fragment library and the importance of differing warhead reactivity. Successful case studies from the world of drug discovery are then be examined.

www.mdpi.com
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JohnTaylor boosted
NeilWithers

Time for that #introduction:

I'm Neil, I'm the features #editor on #ChemistryWorld and I commission, edit and publish the long articles, normally about one a week.

Here's this week's, on the #hormones behind what makes you #hangry
chemistryworld.com/features/th

Maybe I'll move the #tractors account over later...

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JohnTaylor boosted
Bala Hota MD MPH

#Introduction
Just migrated to a new instance on med-mastodon -

I am an Infectious Diseases physician and Clinical Informaticist in the Chicago area. I have been with Tendo since January 2022, an early stage company in the patient experience space, building out our analytics capability.

I have had research interests over the years in healthcare quality (and the flaws with how it is measured) and use of data in healthcare. #informatics #interoperability #quality #outcomes

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JohnTaylor boosted
Gerling-Driessen Lab

#introduction to our work. Trained as an organic chemist, I found my passion for #glycotime working with @bertozzi at stanford university on understanding #raredisease #NGLY1 deficiency during my postdoc. With my team, currently located at Heinrich Heine University in Duessendorf, I use #bioorthogonal chemistry to study aberrant #glycosylation in congenital disorders of glycosylation and some types of cancer. We develop multi-modal chemical probes for #imaging and #glycoproteimics

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JohnTaylor boosted
Julie Petro

#introduction
Hi! I'm the Director of Communications at ORCID. If you're in research, you may know of us: we uniquely identify & connect researchers & innovators to their affiliations and contributions across disciplines, borders, and time.

I have a long history in #SciComms. When I'm not doing that, I'm working on my first novel or planning my next concert adventure.

I love ORCID's values of Openness, Trust, and Inclusivity. I'm also keen on kindness & collegiality which is why I'm here. 😀

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JohnTaylor boosted
Fleur M. Ferguson

Hi everyone, I’m new to mastodon and figuring out how to use this new platform. I’m Fleur Ferguson, a chemical biology professor at UC San Diego! My lab uses organic chemistry, cell biology and proteomics to interrogate disease signaling and develop next-gen therapeutics! #ChemicalBiology #targetedproteindegradation #newPI

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JohnTaylor boosted
Cedric Graebin

#introduction

Hi there! My name is Cedric and I'm a synthetic medicinal chemist. I design and develop new molecules hoping to find something useful to treat neglected tropical diseases such as #Malaria, #Leishmaniasis and #Chagas disease.

Currently I am a #MedicinalChemistry trainer at the Wellcome Centre for Anti-Infectives Research at the University of Dundee, Scotland. My interests are #chemistry, #DrugDesign, #compchem and some #python on the side.

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JohnTaylor boosted
Dave nλ=2dsinθ

Hi #Science #structuralbiology people.

The lab I work in at the Crick has a #PhD studentship available starting Autumn 2023, deadline for application is *Thursday* 10th Nov 12noon GMT

The project involves structural investigation of receptor tyrosine kinase signalling complexes. Main techniques include #CryoEM and #crystallography.

Details here: crick.ac.uk/careers-study/vaca

Please Boost! #phdchat

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JohnTaylor

Interesting read - pretty compelling evidence of a mechanistic link between fractures and bone mets in cancer patients

the-scientist.com/news-opinion

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JohnTaylor boosted
Ellis Crawford

Highlighting a new cross-journal Editor's Choice collection celebrating Professor Malika Jeffries-EL joining Chemical Science as an Associate Editor!

Malika has always been excited by chemistries that push the boundaries in the pursuit of complex materials and the optimization of their properties.

The selection features experimental and theoretical work leading to new materials for use in a range of applications.

#chemistry #OrganicElectronics #OrganicSemiconductors

ow.ly/UUtA50LvVXQ

A portrait photograph of Professor Malika Jeffries-EL
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JohnTaylor boosted
Anne_Imberty

RT @InnoglyA@twitter.com

Thanks @Glycopedia@twitter.com for the link to the recent @ACSChemRev@twitter.com on GlycoSciences

#glycotime

glycopedia.eu/news/article/che

🐦🔗: twitter.com/InnoglyA/status/15

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JohnTaylor boosted
Jean-Philip Piquemal

I did not introduce myself after setling up in #Mastodon. I am Professor of Chemistry at Sorbonne Université in Paris. Technically, I am a quantum chemist but I learned a while back ago that molecules do move over time...(incredible!). I am therefore interested in Multiscale Quantum Chemistry and Molecular Simulation. My group's research is performed in strong interdisciplinary interactions with Applied #Maths & #HPC.
#compchem #supercomputing #quantumcomputing #machinelearning

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