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...

In collaboration with @mattevilab.bsky.social, we share in @naturecomms.bsky.social our work studying the mechanism of LSD1 covalent ‘formylators’. Many LSD1 inhibitors create a bulky FAD-drug adduct. Discovered by Takeda by phenotypic screening, these formylators serendipitously create formyl-FAD.

I’m excited to share the latest work from our lab, led by a group of three amazing scientists: Junbing Zhang, Yousuf Ali and Harrison Chong, who describe @nature the discovery of a ROS sensor, VPS35, which links cytosolic H2O2 levels to regulation of mitochondrial translation and

Thanks Johannes!

Interested in small molecule mechanism? If you’re at #ACSSpring2025, stop by the Eli Lilly Symposium Wed 9am–12pm @ Room 31A in the convention center. Cool talks from @michael-erb.bsky.social, Yuh Min Chook & @xiaoyuzhang.bsky.social. I’ll discuss our program on chemical genomics. Come check it out!

Congratulations Jeremy!!

Delighted to share this work led by @mekedlawitts.bsky.social that investigates the delivery efficiency of various protein delivery vehicles! pubs.acs.org/doi/10.1021/...

Congratulations!!

Happy to share a @nature.com News and Views on the amazing discoveries by @brianliau.bsky.social & Ning Zheng labs on how a molecular glue unexpectedly mimics the effect of cancer mutations. Such cool science and with implications to drug discovery. Check it out. www.nature.com/articles/d41...

Thanks Michael!

Thanks for the help!

Thanks!

Thanks Steven!

Thanks Carolyn!

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

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...

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...

Today in @nature.com we share our back-to-back stories with Ning Zheng’s lab revealing chemical-genetic convergence between a molecular glue degrader & E3 ligase cancer mutations. 1/5