Steven Corsello
@corsello.bsky.social
Physician scientist and oncologist at Stanford. Phenotypic drug discovery for cancer. https://corsellolab.stanford.edu/
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
September 2, 2025 at 6:39 PM
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
September 2, 2025 at 6:39 PM
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
@damonrunyon.org
theNCI
@stanford-cancer.bsky.social
@stanfordmedicine.bsky.social
@stanford-chemh.bsky.social
and generous donors. 16/18
September 2, 2025 at 6:39 PM
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
@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
September 2, 2025 at 6:39 PM
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
September 2, 2025 at 6:39 PM
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
September 2, 2025 at 6:39 PM
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
September 2, 2025 at 6:39 PM
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
September 2, 2025 at 6:39 PM
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
September 2, 2025 at 6:39 PM
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
September 2, 2025 at 6:39 PM
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
September 2, 2025 at 6:39 PM
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
September 2, 2025 at 6:39 PM
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
September 2, 2025 at 6:39 PM
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
September 2, 2025 at 6:39 PM
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
September 2, 2025 at 6:39 PM
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
September 2, 2025 at 6:39 PM
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
2/18
Defining the antitumor mechanism of action of a clinical-stage compound as a selective degrader of the nuclear pore complex
Abstract. Cancer cells are acutely dependent on nuclear transport due to elevated transcriptional activity, suggesting an unrealized opportunity for selective therapeutic inhibition of the nuclear por...
aacrjournals.org
September 2, 2025 at 6:39 PM
Cancer Discovery manuscript link: aacrjournals.org/cancerdiscov...
2/18
2/18
Reposted by Steven Corsello
September 2, 2025 at 2:35 PM
Hi! We work on new therapies.
November 24, 2024 at 6:22 PM
Hi! We work on new therapies.