Brian Liau
@brianliau.bsky.social
Chemical biologist broadly defined
We show that the FAD-drug adduct undergoes a Grob fragmentation to create formyl-FAD. We then show how mutations in LSD1 can promote fragmentation & drug resistance in leukemia cells, expanding our views on resistance mechanisms. An awesome trans-Atlantic team effort!
www.nature.com/articles/s41...
www.nature.com/articles/s41...
Covalent adduct Grob fragmentation underlies LSD1 demethylase-specific inhibitor mechanism of action and resistance - Nature Communications
Next generation precision lysine-specific histone demethylase 1A (LSD1) covalent inhibitors which selectively block LSD1 enzyme activity by forming a compact N-formyl-FAD adduct have been developed, b...
www.nature.com
April 3, 2025 at 12:00 PM
We show that the FAD-drug adduct undergoes a Grob fragmentation to create formyl-FAD. We then show how mutations in LSD1 can promote fragmentation & drug resistance in leukemia cells, expanding our views on resistance mechanisms. An awesome trans-Atlantic team effort!
www.nature.com/articles/s41...
www.nature.com/articles/s41...
Congratulations Jeremy!!
March 23, 2025 at 11:05 PM
Congratulations Jeremy!!
Thanks for the help!
February 13, 2025 at 12:17 AM
Thanks for the help!
Most importantly, behind this effort was an incredible team & collaborators: Megan Yeo, Olivia Zhang, Xiaowen Xie, Ceejay Lee, Eunju Nam, N. Connor Payne, Ran Tao, Pallavi Gosavi, Ralph Mazitschek lab, Phil Cole lab, Paul Northcott lab & many others! 5/5
February 12, 2025 at 4:20 PM
Most importantly, behind this effort was an incredible team & collaborators: Megan Yeo, Olivia Zhang, Xiaowen Xie, Ceejay Lee, Eunju Nam, N. Connor Payne, Ran Tao, Pallavi Gosavi, Ralph Mazitschek lab, Phil Cole lab, Paul Northcott lab & many others! 5/5
Taken together, this paradigm of chemical-genetic convergence raises the broader prospect that we can use mutational scanning approaches to uncover glue-able and/or functional protein sites to then prioritize for small molecule development. 4/5
February 12, 2025 at 4:20 PM
Taken together, this paradigm of chemical-genetic convergence raises the broader prospect that we can use mutational scanning approaches to uncover glue-able and/or functional protein sites to then prioritize for small molecule development. 4/5
In story 2, we uncover how neomorphic cancer mutations in KBTBD4, a recurrently mutated E3 ligase substrate receptor in medulloblastoma, structurally & functionally mimic UM171. This reveals how chemical & genetic neomorphs can act by the same mechanism. 3/5
www.nature.com/articles/s41...
www.nature.com/articles/s41...
www.nature.com
February 12, 2025 at 4:20 PM
In story 2, we uncover how neomorphic cancer mutations in KBTBD4, a recurrently mutated E3 ligase substrate receptor in medulloblastoma, structurally & functionally mimic UM171. This reveals how chemical & genetic neomorphs can act by the same mechanism. 3/5
www.nature.com/articles/s41...
www.nature.com/articles/s41...
In story 1, we unravel the mechanism of UM171, a small molecule cold case that acts by 'serendegrity'. Using chemical genomics & structural biology, we show UM171 is the 1st glue to reprogram a dimeric E3 ligase, engaging HDAC1/2 to degrade the CoREST complex. 2/5
www.nature.com/articles/s41...
www.nature.com/articles/s41...
www.nature.com
February 12, 2025 at 4:20 PM
In story 1, we unravel the mechanism of UM171, a small molecule cold case that acts by 'serendegrity'. Using chemical genomics & structural biology, we show UM171 is the 1st glue to reprogram a dimeric E3 ligase, engaging HDAC1/2 to degrade the CoREST complex. 2/5
www.nature.com/articles/s41...
www.nature.com/articles/s41...