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...

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.

Oxidation of retromer complex controls mitochondrial translation - Nature Systematic base-editing and computational screens identify specific cysteine residues on VPS35 in the retromer complex as key sensors that decrease mitochondrial translation in response to reactive ox...

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!!

Engineering Cell-Specific Protein Delivery Vehicles for Erythroid Lineage Cells Biologics such as proteins, peptides, and oligonucleotides are powerful ligands to modulate challenging drug targets that lack readily accessible and “ligandable” pockets. However, the limited membran...

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!!

Molecular glue unexpectedly mimics the effect of cancer mutations Protein structures could guide the design of molecular glue degraders.

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