Dow Lab
@dowlab.bsky.social
Desperately trying to understand the cancer genome
KRAS | WNT | CRISPR | Base editing
Sometimes building guitars
www.dowlab.org
KRAS | WNT | CRISPR | Base editing
Sometimes building guitars
www.dowlab.org
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!!
a close up of a man 's face with the words care to share below him
ALT: a close up of a man 's face with the words care to share below him
media.tenor.com
March 12, 2025 at 4:08 PM
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).
March 12, 2025 at 4:08 PM
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).
March 12, 2025 at 4:08 PM
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
March 12, 2025 at 4:08 PM
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
March 12, 2025 at 4:08 PM
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
March 12, 2025 at 4:08 PM
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...
March 12, 2025 at 4:08 PM
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...
a little girl is asking why not both while standing in a kitchen .
ALT: a little girl is asking why not both while standing in a kitchen .
media.tenor.com
March 12, 2025 at 4:08 PM
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...
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!
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!
March 9, 2025 at 12:14 PM
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!
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!