Kyle Cottrell
@kylecottrell.bsky.social
Father | Assistant Professor @PurdueBiochem (RNA editing and regulation) | Postdoc & PhD @WUSTL | MS & BS @MissouriState | #firstgen #NewPI #NIHMOSAIC K99/R00 (posts and comments are my own and do not reflect my employer)
Here is the post thread describing the work. bsky.app/profile/kyle...
Here is the post thread I promised: We have been interested in ADAR1 as a therapeutic target for triple-negative breast cancer for a while. That project was supported by the NIH before Trump terminated it, but that is another story. While ADAR1 is a promising target - there aren't any inhibitors 1/n
Our second preprint is out today! Post thread to come later.
September 18, 2025 at 3:04 PM
Here is the post thread describing the work. bsky.app/profile/kyle...
The mini pie in this case is technically a galette - with strawberry jam.
September 6, 2025 at 11:48 PM
The mini pie in this case is technically a galette - with strawberry jam.
This is my first research article as sole corresponding author and the first research article from the Cottrell lab. I'm very happy that it ended up at RNA. This is my first time publishing in RNA and this was by far my best review experience to date. Huge thanks to editor and reviewers!
August 14, 2025 at 2:33 PM
This is my first research article as sole corresponding author and the first research article from the Cottrell lab. I'm very happy that it ended up at RNA. This is my first time publishing in RNA and this was by far my best review experience to date. Huge thanks to editor and reviewers!
The other authors on this preprint are both undergraduates in the lab. Estelle Gardner performed the in vitro A-to-I editing assay, and is responsible for getting this assay up and running in the lab. Renee Chua helped with the A-to-I editing analyses. 8/8
August 13, 2025 at 4:35 PM
The other authors on this preprint are both undergraduates in the lab. Estelle Gardner performed the in vitro A-to-I editing assay, and is responsible for getting this assay up and running in the lab. Renee Chua helped with the A-to-I editing analyses. 8/8
In the end, our data do not support ZYS-1 as an ADAR1 inhibitor. Our findings are also consistent with those reported in another preprint www.biorxiv.org/content/10.1.... This is the first, first author manuscript preprint from graduate student Cassandra Smoak - who joined the lab this spring 7/n
Re: Concerns Regarding the Validation of ZYS-1 as a Bona Fide ADAR1 Inhibitor
Wang et al. in Nature Cancer report ZYS-1 as an ADAR1 inhibitor and present biochemical and cellular evidence to support ZYS-1’s direct interaction with and inhibition of ADAR1, including enzymatic as...
www.biorxiv.org
August 13, 2025 at 4:35 PM
In the end, our data do not support ZYS-1 as an ADAR1 inhibitor. Our findings are also consistent with those reported in another preprint www.biorxiv.org/content/10.1.... This is the first, first author manuscript preprint from graduate student Cassandra Smoak - who joined the lab this spring 7/n
Finally, we evaluated A-to-I editing both in cells treated with ZYS-1 or in vitro. We assessed three different A-to-I edit sites in four cell lines. With only one exception, ZYS-1 treatment did not reduce A-to-I editing in cells. We observed the same in vitro with purified ADAR1 and 5-HT2C RNA. 6/n
August 13, 2025 at 4:35 PM
Finally, we evaluated A-to-I editing both in cells treated with ZYS-1 or in vitro. We assessed three different A-to-I edit sites in four cell lines. With only one exception, ZYS-1 treatment did not reduce A-to-I editing in cells. We observed the same in vitro with purified ADAR1 and 5-HT2C RNA. 6/n
We next asked if ZYS-1 could phenocopy ADAR1 depletion. Depletion of ADAR1 in ADAR1-dependent cell lines by knockout or knockdown causes activation of PKR and induction of interferon stimulated genes. ZYS-1 treatment generally did neither in the cell lines that we evaluated. 5/n
August 13, 2025 at 4:35 PM
We next asked if ZYS-1 could phenocopy ADAR1 depletion. Depletion of ADAR1 in ADAR1-dependent cell lines by knockout or knockdown causes activation of PKR and induction of interferon stimulated genes. ZYS-1 treatment generally did neither in the cell lines that we evaluated. 5/n
We found that ZYS-1 killed ADAR1-dependent (those that die upon ADAR1 depletion) and ADAR1-independent cells with very similar EC50s. ZYS-1 also killed ADAR1 knockout cells as well as WT cells. 4/n
August 13, 2025 at 4:35 PM
We found that ZYS-1 killed ADAR1-dependent (those that die upon ADAR1 depletion) and ADAR1-independent cells with very similar EC50s. ZYS-1 also killed ADAR1 knockout cells as well as WT cells. 4/n
Recently, ZYS-1 was reported to inhibit ADAR1 www.nature.com/articles/s43.... Given our past experience evaluating putative ADAR1 inhibitors, we decided to put ZYS-1 through a series of tests. First, we asked if ZYS-1 is more cytotoxic to ADAR1-dependent vs ADAR1-independent cells. 3/n
Targeting ADAR1 with a small molecule for the treatment of prostate cancer - Nature Cancer
Yang and colleagues present a small-molecule inhibitor for ADAR1 and show that its use is therapeutically beneficial in the context of prostate cancer.
www.nature.com
August 13, 2025 at 4:35 PM
Recently, ZYS-1 was reported to inhibit ADAR1 www.nature.com/articles/s43.... Given our past experience evaluating putative ADAR1 inhibitors, we decided to put ZYS-1 through a series of tests. First, we asked if ZYS-1 is more cytotoxic to ADAR1-dependent vs ADAR1-independent cells. 3/n
ADAR1 carries out A-to-I editing of RNA. Its substrate is dsRNA. Previous groups have reported adenosine analogues as a ADAR1 inhibitors, but we have found those not to be selective inhibitors of ADAR1 aacrjournals.org/cancerrescom... 2/n
www.nature.com
August 13, 2025 at 4:35 PM
ADAR1 carries out A-to-I editing of RNA. Its substrate is dsRNA. Previous groups have reported adenosine analogues as a ADAR1 inhibitors, but we have found those not to be selective inhibitors of ADAR1 aacrjournals.org/cancerrescom... 2/n