Lightnews — Scholar-powered news

Geordi Frere @geordifrere.bsky.social · Apr 28

Why does the donut display at the Buffalo airport Timmies look better than any I've seen in Canada?

Geordi Frere @geordifrere.bsky.social · Apr 26

I've got to try it sometime! So many interesting facets to this mechanism: N-to-O acyl shift to the diazoacetate (not sure if intramolecular as Huisgen proposed or if intermolecular between identical N-nitrosoamides), benzylic methyl activation, and a cool cyclization step!
doi.org/10.1002/jlac...

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Geordi Frere @geordifrere.bsky.social · Apr 26

Now for the mechanistic discussion: do you think this reaction proceeds through intramolecular benzylic activation followed by nitrene formation and cyclization, or through diazotization followed by deprotonation by acetate and cyclization?

Geordi Frere @geordifrere.bsky.social · Apr 26

References:

Jacobsen & Huber (1908) doi.org/10.1002/cber...

Huisgen & Nakaten (1954) doi.org/10.1002/jlac...

Huisgen & Bast (1962) orgsyn.org/demo.aspx?pr...

Organic Syntheses Procedure CV5P0650

orgsyn.org

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Geordi Frere @geordifrere.bsky.social · Apr 26

An #organicchemistry mechanistic puzzle for your Saturday morning coffee: the Jacobsen-Huisgen indazole synthesis! This reaction was used to synthesize Lilly's oral GLP-1 agonist orforglipron (patents.google.com/patent/US202...). Take a crack at the mechanism, then see the question below!

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Geordi Frere @geordifrere.bsky.social · Mar 23

New preprint by Chris Parker on target-agnostic PROTACs comprising diverse target-binding moieties linked to a CRBN ligand to explore the degradable proteome. Proteomic profiling identified >50 proteins that were degraded by this library, revealing potential starting points for PROTAC development.

Proteome-Wide Discovery of Degradable Proteins Using Bifunctional Molecules

Targeted protein degradation (TPD) is an emergent therapeutic strategy with the potential to circumvent challenges associated with targets unamenable to conventional pharmacological inhibition. Among ...

www.biorxiv.org

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Geordi Frere @geordifrere.bsky.social · Mar 14

A crystal structure of tubulin-RB3 bound to a colchicine site inhibitor showed another binding site at the RB3 interface. An optimized compound with no colchicine site affinity retained antimicrotubule activity through stathmin complex stabilization. #inducedproximity #molecularglues

Optimized tumabulin is selective for the new site

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Geordi Frere @geordifrere.bsky.social · Mar 14

A new paper in PNAS identifies tumabulin-2 as a #molecularglue targeting the tripartite interface of α-tubulin, β-tubulin, & RB3 to elicit a novel mechanism of microtubule disruption via stabilization of a polymer-incompatible complex & sequestration of tubulin dimers!
www.pnas.org/doi/10.1073/...

Crystal structure of tumabulin with tubulin-RB3 reveals a novel binding site and molecular glue mechanism

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Geordi Frere @geordifrere.bsky.social · Mar 11

Importantly, the authors don't observe alkylamine biotransformation into an electrophilic aldehyde as has been reported for other FBXO22-recruiting #degraders.

Geordi Frere @geordifrere.bsky.social · Mar 11

Although this reaction proceeds in a SMARCA-independent manner in vitro (potentially due to artificially high compound & protein concentrations), the true event may proceed through template-assisted #covalent modification, akin to the DCAF16-recruiting BRD4 degraders of Nathanael Gray et al.

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Geordi Frere @geordifrere.bsky.social · Mar 11

Using an unconventional 2-alkynylpyridine warhead, G-6599 covalently engages cysteines (predominantly C228 and C326) in FBXO22 to facilitate SMARCA2/4 degradation.

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Geordi Frere @geordifrere.bsky.social · Mar 11

Researchers at Genentech published an interesting preprint describing the discovery of a #monovalent electrophilic #degrader of SMARCA2/4 that acts as a #molecularglue mediating an interaction with "frequent hitter" E3 ligase FBXO22.
www.biorxiv.org/content/10.1...

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Geordi Frere @geordifrere.bsky.social · Mar 4

The increased thermal stability of BEHT triflate over azodicarboxylates, combined with its long-term shelf stability, commercial availability, and expanded nucleophile scope should translate into sweeping uptake by industry!

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Geordi Frere @geordifrere.bsky.social · Mar 4

A major breakthrough for the Mitsunobu reaction! New work from the Charette lab at UMontreal reports a universal Mitsunobu reagent with no limitation on nucleophile pKa, expanding substrate scope to include primary & secondary amines that were previously incompatible with this reaction!

Universal Reagent for Mild and Stereospecific Nucleophilic Substitution of Alcohols with Amines

A user-friendly, shelf-stable protonated betaine reagent (BEHT triflate), derived from Mitsunobu reagents, has been developed to enable the direct displacement of alcohols using primary and secondary...

onlinelibrary.wiley.com

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Geordi Frere @geordifrere.bsky.social · Feb 11

"Courts halt appeal Trump unfreeze to cash immediate all order administration required federal"

Geordi Frere @geordifrere.bsky.social · Feb 11

This is the most convoluted headline I've ever read
apnews.com/article/trum...

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Geordi Frere @geordifrere.bsky.social · Jan 28

Funding stagnation has rendered Canada uncompetitive in global biomedical research, and further fuels the accelerating exodus of scientists from Canada. Quelling this tide requires systemic increases to CIHR grants and equitable financial support for all academic trainees.

Two decades of stagnant funding have rendered Canada uncompetitive in biomedical research. Here’s why it matters, and how to fix it. - Academic Matters

academicmatters.ca

Geordi Frere @geordifrere.bsky.social · Jan 28

For many scientific trainees, the prospect of pursuing a Canadian postdoc's meager salary is financially daunting at best and laughable at worst, causing leading Canadian institutions to miss out on top talent.

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Geordi Frere @geordifrere.bsky.social · Jan 28

In the same period, the success rate for CIHR grants has decreased from 33% to just 19%, and the cost of lab supplies continue to skyrocket.

Canada's CIHR budget is 50 times lower than that of the NIH, while our population is only nine times smaller than the US.

This link will take you to a page that’s not on LinkedIn

lnkd.in

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Geordi Frere @geordifrere.bsky.social · Jan 28

Even after the much-needed increase in CIHR scholarship stipends, fewer than 10% of grad students and postdocs receive these awards. All other trainees rely upon funding supplemented by their supervisors, drawing from CIHR funding that hasn't increased in 20 years.
www.nature.com/articles/d41...

Canada’s postgraduate funding gap is still yawning even after budget increases

Letter to the Editor

www.nature.com

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Geordi Frere @geordifrere.bsky.social · Jan 24

In a new paper in @naturechemistry.bsky.social, Patrick Barth & colleagues use solvent-mediated allosteric network models to design synthetic adenosine receptors with high signalling activity & thermostability that crystallize in an active-like state without G protein!
www.nature.com/articles/s41...

Computational design of highly signalling-active membrane receptors through solvent-mediated allosteric networks - Nature Chemistry

Solvent-mediated interaction networks control a wide range of protein functions, but their design has been neglected owing to a lack of accurate computational tools. Now it is shown that allosteric si...

www.nature.com

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Geordi Frere @geordifrere.bsky.social · Jan 20

Michael: "Janet, could you draw the mechanism for the Dess-Martin oxidation?"

Janet: "Here you go!"

Michael: *long pause, resigned nod* "...Thank you, Janet."

Abysmal DALL-E attempt at the Dess-Martin oxidation mechanism.

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Geordi Frere @geordifrere.bsky.social · Jan 4

On top of the usual suspects, they evaluate inhibitors of the deneddylase CSN, the Ub receptor Rpn13, & the unfoldase VCP/p97 as controls for degradation rescue studies. They also show that the E1 inhibitor PYR-41 did not rescue degradation at any dose tested, recommending TAK-243 for this purpose.

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Geordi Frere @geordifrere.bsky.social · Jan 4

A rigorous study of UPS tool compounds for #degrader evaluation is published by Stefan Knapp @thesgc.bsky.social in ACS Chemical Biology! They determine the optimal doses of UPS pathway inhibitors that rescue degradation without displaying off-target activity and toxicity.
dx.doi.org/10.1021/acsc...

Functional Characterization of Pathway Inhibitors for the Ubiquitin-Proteasome System (UPS) as Tool Compounds for CRBN and VHL-Mediated Targeted Protein Degradation

Small molecule degraders such as PROteolysis TArgeting Chimeras (PROTACs) and molecular glues are new modalities for drug development and important tools for target validation. When appropriately opti...

dx.doi.org

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Geordi Frere @geordifrere.bsky.social · Dec 29

A new paper in #JACS @acsjacs.bsky.social employs aldehyde cyclization chemistry to orthogonally double-label proteins at N-terminal and intra-chain cysteines with paramagnetic tags, allowing the authors to study protein oligomerization using EPR distance measurements.
pubs.acs.org/doi/10.1021/...

Efficient Orthogonal Spin Labeling of Proteins via Aldehyde Cyclization for Pulsed Dipolar EPR Distance Measurements

Pulsed dipolar electron paramagnetic resonance (PD-EPR) measurement is a powerful technique for characterizing the interactions and conformational changes of biomolecules. The extraction of these dist...

pubs.acs.org

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