No time for a #bluetorial today, but happy to share a new preprint from the lab. In this paper we used gene saturation and cancer-mutation-focused base editing screens to unveil genetic drivers of resistance to multiple KRAS inhibitors. www.biorxiv.org/content/10.1...
I promise this is a science account and we have multiple papers brewing, but for now… latest guitar is finished!! This one is my own design and built entirely from scratch. Took ~6 months as my real job kept getting in the way…
This is amazing!!
Huge thanks to everyone who contributed to this work over the years, including many of whom are not on bsky... as I wasn't until last week 😬. Also, since I'm a newbie here, please share widely!!
The selective profile was maintained over 3 weeks of drug exposure and we saw equivalent selective growth inhibition of APC/KRAS/p53 mutant organoids. TLDR: the small molecule shows activity in all WNT-dependent contexts, provided TNKS is lost (het or hom).
Similar story when you look at organoid growth. The lead molecule (TDI-012804) shows anti-proliferative activity in both TNKS knockout and heterozygous cells (hets having an intermediate response compared to WT).
In APC-mutant intestinal organoids, the molecule performs very well, inducing a classic pan-TNKS inhibitor (G007-LK) transcriptional response in TNKS knockout cells, but having virtually no effect in the TNKS WT context
With amazing support from Brandon Malone and Rich Hite at @mskcancercenter.bsky.social, we resolved the cryoEM structure of the lead molecule bound to TNKS2 and propose a mechanism for the preferential binding of this compound to TNKS2 over TNKS1
So, Jill teamed up with the TRI-I Therapeutics Discovery Institute at @weillcornell.bsky.social and using structure-guided design, generated and individually screened hundreds of compounds. Ultimately, she found a handful of potent and selective molecules
Turns out that the TNKS locus is on the short arm of chromosome 8, which is frequently lost in advanced epithelial cancers. The hets also show reduced expression, which would theoretically make them sensitive to TNKS2 blockade. Unfortunately, there were no good TNKS2 selective compounds...
The whole thing started after an accidental and surprising discovery that some cancer cell lines show a molecular response to silencing of the TNKS2 enzyme, whereas most require suppression of both TNKS1 and TNKS2...
New preprint time!!
This one has been brewing in the lab for ~8 years describes a strategy for tumor selective WNT suppression. It was led by an amazing (then) grad student, Jill Zimmerman, with help from a host of lab members and collaborators along the way.
www.biorxiv.org/content/10.1...
More pics for @chrmosimann.bsky.social @wbderry.bsky.social @lucksmith.bsky.social
Still have to carve the neck, and sand for days, but almost ready for finish! Excited to hear this one - the tap tone sounds really nice!
On the old bird app, I promised to post updates on the latest guitar build… I failed, but will make up for lost time here. This one is a custom design, larger body (modified grand symphony), koa top back and sides, ebony binding and fretboard, and a bunch of abalone (for the Hawaiian island vibe).
Hello, bsky! First post is fun one - Today I moved to Professor with tenure at @weillcornell.bsky.social! Huge thanks to everyone who has contributed to our efforts over the last decade. It takes a village! Looking forward to more science and guitar building posts on #newoldtwitter.