Great piece on @corsello.bsky.social and coworkers’ exciting new discovery @stanfordmedicine.bsky.social

Great 💎s on GI cancers at #CCRTP25 @stanford-cancer.bsky.social @corsello.bsky.social

-drug discovery w better yield from unexpected hits, then subsequently modified
-negative results so important to publish
-environmental factors like weight most likely culprits of young onset colon cancer

We are also recruiting a new postdoc. If you are excited to work at the interface of functional genomics and chemical biology, please contact me to learn more! 18/18

We thank the reviewers and editorial staff at @aacrjournals.bsky.social , and our collaborators @stanfordmedicine.bsky.social , @broadinstitute.org and @wertheimufscripps.bsky.social. 17/18

Many more details in the paper linked above. We are grateful for support from:
@damonrunyon.org
theNCI
@stanford-cancer.bsky.social
@stanfordmedicine.bsky.social
@stanford-chemh.bsky.social
and generous donors. 16/18

TRIM21 molecular glues are emerging as an exciting research area, and our findings are complemented by excellent recent work from Ting Han, Drew Adams, and Dengfeng Dou as well as foundational work from Leo James. 15/18

Most encouragingly, we observed robust TRIM21 molecular glue activity against pancreatic cancer xenografts and patient-derived PDAC organoid models. 14/18

How does blocking the nuclear pore trigger apoptosis? One factor is that cancer cells are addicted to a constant stream of short-lived pro-survival mRNAs. Starving the cell of key survival signals results in rapid cell death. 13/18

Why is this so effective against cancer? Prior work shows that when the nuclear pore is disrupted, cancer cells tend to die via apoptosis, while normal cells can recover. This suggests a potential therapeutic window supported by our findings with immortalized cells. 12/18

We then confirmed the crucial link. Using multiple assays (NanoBiT in cells, TR-FRET in vitro), we demonstrated that the compound induces physical proximity between TRIM21 and NUP98. 11/18

We went back to our original CRISPR KO screen and realized that a single guide (out of 4) against NUP98 conferred strong resistance to drug activity. This was missed at the gene summary level! The active guide uniquely targeted the NUP98 autoproteolytic domain (APD). 10/18

TRIM21 is a ubiquitin ligase that labels other proteins for destruction. To identify its substrates, we performed extensive proteomic profiling and proximity labeling which demonstrated degradation of nuclear pore complex proteins. 9/18

With TRIM21 as our likely molecular target, we performed a tiled base editing screen, which helped map the compound binding site to the PRYPSRY domain. Direct compound binding to recombinant TRIM21 PRYSPRY was confirmed via SPR and crystallography. 8/18

In a fantastic collaboration with Nathanael Gray's lab, we developed new derivatives that were >10-fold more potent, while still being highly selective and completely dependent on TRIM21 for their activity. 7/18

Next, we conducted genome-scale CRISPR KO and activation modifier screens yielding TRIM21 and IRF genes as the top functional mediators of drug response across the entire genome. 6/18

The compound was re-tested in full dose-response across ~900 cell lines, yielding TRIM21 mRNA expression as the top predictive biomarker. Activity was also enriched against pancreatic and head & neck cancers. 5/18

Our story begins with cell line viability profiling via the PRISM Drug Repurposing Project @CancerDepMap. We found that a former clinical drug candidate, an erastin derivative (PRLX-93936), showed highly selective anticancer activity. 4/18

In work led by Linjie Yuan, Wenzhi Ji, and Brendan Dwyer, we employed large-scale phenotypic profiling, genetic modifier screens, and proteomics to discover that a prior clinical-stage drug acts as a TRIM21 molecular glue to degrade the nuclear pore complex. 3/18

Cancer Discovery manuscript link: aacrjournals.org/cancerdiscov...
2/18

Excited to share our discovery of potent TRIM21 molecular glues with anticancer activity, online today @CD_AACR: "Defining the antitumor mechanism of action of a clinical-stage compound as a selective degrader of the nuclear pore complex". 1/18

@stanfordmedicine.bsky.social

Good morning Monterey 🌞 Nothing like multidisciplinary discussion of GI cancers to kick off another sunny morning next to the Pacific with Lipika Goyal and Pam Basto @stanford-cancer.bsky.social reviewing 8(!!) new approvals for GI cancers 🌊

Great meeting @ ANCO branch of @ascocancer.bsky.social 🤓

Today we report that an engineered skin bacterium, swabbed gently on the head of a mouse, can unleash a potent antibody response against a pathogen. Could lead to topical vaccines that are applied in a cream. @djenetbousbaine.bsky.social led the charge... @natureportfolio.bsky.social 1/55

@pollyfordyce.bsky.social @stanford-chemh.bsky.social is officially a household name. That is some real impact!

Stanford Hematology has launched a physician scientist search! Research program can be lab-based and/or translational. facultypositions.stanford.edu/en-us/job/49...

Hi! We work on new therapies.

Checking out the science community on Bluesky!