Steven Cheng

Microbiome metabolism of dietary phytochemicals controls the anticancer activity of PI3K inhibitors Diet can impact anticancer drug activity. A classic example in rodents is a ketogenic diet enhancing PI3K inhibitor activity. Here, we show that phytochemicals and their microbiome derivatives, rather...

www.cell.com/cell/abstrac...

"Here, we confirm profound diet-PI3K anticancer synergy but show that it is, surprisingly, unrelated to diet macronutrient composition. Instead, the diet-PI3K interaction involves microbiome metabolism of ingested phytochemicals."

Patient-Specific In Vivo Gene Editing to Treat a Rare Genetic Disease | NEJM Base editors can correct disease-causing genetic variants. After a neonate had received a diagnosis of severe carbamoyl-phosphate synthetase 1 deficiency, a disease with an estimated 50% mortality ...

www.nejm.org/doi/full/10....

"In this study, we describe a personalized base-editing therapy wholly developed in the 6-month span after a patient’s birth."

Small-molecule dissolution of stress granules by redox modulation benefits ALS models - Nature Chemical Biology Uechi et al. found that a small-molecule lipoamide dissolves stress granules (SGs) by targeting SFPQ, a redox-sensitive disordered SG protein, alleviating pathological phenotypes caused by amyotrophic...

www.nature.com/articles/s41...
"Lipoamide partitions into stress granules in cells, prevents formation of stress granules and dissolves existing stress granules, allowing us to identify a pathway that allows stress granules to sense the oxidative state of the cell."

Broad Target Screening Reveals Abundance of FKBP12-Based Molecular Glues in Focused Libraries Competitive (nondegradative) molecular glues represent a promising drug modality that remains underexplored primarily due to the lack of adequate hit identification approaches. In this study, we screened our historically grown FKBP-focused library containing >1000 drug-like molecules to identify FKBP-assisted molecular glues targeting a diverse panel of 57 proteins. In addition to establishing a robust and generalizable screening approach, we discovered three novel FKBP-dependent molecular glues targeting PTPRN, BRD4BD2, and STAT4. Our results demonstrate that molecular glues are more common than previously thought and that they can be identified by repurposing existing focused libraries. An optimized, highly cooperative FKBP12-BRD4BD2 glue demonstrated the involvement of the BD2 pocket and exhibited selectivity over the closely related BD1 domain. Our results underscore the value of FKBP12-assisted molecular glues to target challenging proteins with the potential for high selectivity.

Broad Target Screening Reveals Abundance of FKBP12-Based Molecular Glues in Focused Libraries
pubs.acs.org/doi/10.1021/...

"Our results demonstrate that molecular glues are more common than previously thought and that they can be identified by repurposing existing focused libraries."

Excited to share Benson’s and Maria’s work in collab w/Kostas Tzelepis: we found the nucleolar protein NPM1 is a marker of AML and can be targeted therapeutically

connecting ‘cell surface RNA biology’ to cancer biology

@natbiotech.nature.com
www.nature.com/articles/s41...

Therapeutic potential of allosteric HECT E3 ligase inhibition
www.cell.com/cell/fulltex...

"we discover inhibitors that bind a cryptic cavity distant from the catalytic cysteine"
...
"these inhibitors restrict an essential catalytic motion by extending an α helix over a conserved glycine hinge"

Very interesting screening approach leveraging different technologies including DELs, photocleavable linkers, microfluidics, RNA-seq to discover new bioactive VHL molecular glues

Discovery of a VHL molecular glue degrader of GEMIN3 by Picowell RNA-seq Targeted protein degradation (TPD) is an emerging therapeutic modality in which small molecules are used to recruit targets to the natural protein degradation machinery of the cell. Molecular glue deg...

🚨 Rational discovery of VHL molecular glues. New Preprint from @amgen.bsky.social Induced Proximity group led by postdoc Jonathan Bushman reports the discovery of a VHL molecular glue degrader of GEMIN3 by Picowell RNA-seq. Read on for details. 🧵1/8 www.biorxiv.org/content/10.1...

www.nature.com/articles/s41...
www.nature.com/articles/d41...

A polyene macrolide targeting phospholipids in the fungal cell membrane

New antifungal breaks the mould

"Mandimycin is an antifungal molecule that acts by specifically targeting phospholipids"

Small-molecule allosteric activator of ubiquitin-specific protease 7 (USP7) https://www.biorxiv.org/content/10.1101/2025.03.14.643379v1

Molecular glues that inhibit deubiquitylase activity and inflammatory signaling - Nature Structural & Molecular Biology The BRCC36 isopeptidase complex (BRISC) is a deubiquitylase that stabilizes interferon receptors, driving inflammation. We discovered ‘BRISC molecular glue’ inhibitors (BLUEs) that selectively inactiv...

www.nature.com/articles/s41...
Neat story of hit validation

To further validate the compound in well H20, we purchased.. from two commercial vendors.. neither inhibited..

LC–MS revealed that the H20 compound was pure, with a mass of 555.55 Da instead of the expected mass of 382.25 Da

A pharmacological modality to sequester homomeric proteins Molecules that can perturb protein-protein interactions have an immense impact on chemical biology and therapeutics. However, such compounds typically rely on accessory proteins to function, such as E...

www.biorxiv.org/content/10.1...

"We target homomeric proteins with PINCHs (Polymerization Inducing Chimeras) - bifunctional molecules composed of two linked ligands that act as bridges between homomers and trigger their supramolecular assembly into insoluble polymers."

Lysine vitcylation is a vitamin C-derived protein modification that enhances STAT1-mediated immune response Vitamin C directly modifies lysine residues through vitcylation, regulating STAT1 signaling and enhancing anti-tumor immune responses by preventing STAT1 dephosphorylation.

www.cell.com/cell/abstrac...
Lysine vitcylation is a vitamin C-derived protein modification that enhances STAT1-mediated immune response

“Here, we report that vitC directly modifies lysine residues to form “vitcyl-lysine”—a process termed vitcylation.”

Macrophages recycle phagocytosed bacteria to fuel immunometabolic responses - Nature Phagocytosed bacteria can serve as an alternative nutrient source for macrophages, influencing their metabolic and immune responses through the recycling of microbial components, with the process regu...

www.nature.com/articles/s41...

"We are what we eat," said the study's co-senior author Angelo D'Alessandro, Ph.D.

"What we eat changes the composition of us and when immune cells eat bacteria the same thing happens to them."

www.researchsquare.com/article/rs-4...

A clinical drug candidate that triggers non-apoptotic cancer cell death

"[t]his lethal mechanism is distinct from ferroptosis, necroptosis and pyroptosis and requires the lipid metabolic enzyme trans-2,3-enoyl-CoA reductase (TECR)"

🚨 New paper alert! 🚨
Check out our latest work on HypoxyStat, a small-molecule therapy that increases oxygen-hemoglobin affinity and provides a practical form of hypoxia therapy. A great collaboration with Maze Therapeutics
🔗 Paper: doi.org/10.1016/j.ce... @cp-cell.bsky.social

Now online in Cancer Discovery: Restoration of the Tumor Suppressor Function of Y220C-Mutant #p53 by Rezatapopt, a Small Molecule Reactivator - by @PuzioKuter, Lizhong Xu, Masha Poyurovsky, and colleagues doi.org/10.1158/2159...

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

Return to Flatland - Nature Reviews Chemistry Fifteen years ago, an analysis of drug molecules moving through the stages of clinical development suggested that increased three-dimensional character was a marker of greater success. Now, we perform...

Return to Flatland

"Fifteen years ago, an analysis of drug molecules ... suggested that increased three-dimensional character was a marker of greater success. Now, we perform a similar analysis ... to see if the trends observed then still hold today"

www.nature.com/articles/s41...

Modulation of Protein–Protein Interactions with Molecular Glues in a Synthetic Condensate Platform Misregulation of protein–protein interactions (PPIs) underlies many diseases; hence, molecules that stabilize PPIs, known as molecular glues, are promising drug candidates. Identification of novel mol...

Modulation of Protein–Protein Interactions with Molecular Glues in a Synthetic Condensate Platform
pubs.acs.org/doi/10.1021/...

Vertex wins FDA approval for non-opioid pain drug, setting stage for closely watched rollout Vertex Pharmaceuticals won FDA approval for a non-opioid drug for moderate to severe acute pain

Vertex wins FDA approval for non-opioid pain drug, setting stage for closely watched rollout www.statnews.com/2025/01/30/v... via @jonathanwosen.bsky.social

C-terminal amides mark proteins for degradation via SCF–FBXO31 - Nature SCF–FBXO31 scans proteins for C-terminal amidation and marks them for subsequent proteasomal degradation.

🎉Super excited to share our story on how the substrate receptor FBXO31 functions as a quality control factor by recognizing amides. This has been an amazing collaboration between Bode lab and @jcornlab.bsky.social. Special shutout goes to @matthiasmuhar.bsky.social www.nature.com/articles/s41...

Chemoproteomic Profiling of Clickable Fumarate Probes for Target Identification and Mechanism of Action Studies Dimethyl fumarate (DMF) is an established oral therapy for multiple sclerosis worldwide. Although the clinical efficacy of these fumarate esters has been extensively investigated, the mode of action and pharmacokinetics of fumarates have not been fully elucidated due to their broad-spectrum reactivity and complex metabolism in vivo. To better understand the mechanism of action of DMF and its active metabolite, monomethyl fumarate (MMF), we designed and utilized clickable probes to visualize and enrich probe-modified proteins. We further perform quantitative chemoproteomics analysis for proteome-wide target identification and validate several unique and shared targets of DMF and MMF, which provide insight into the reactivity, selectivity, and target engagement of fumarates.

Chemoproteomic Profiling of Clickable Fumarate Probes for Target Identification and Mechanism of Action Studies
pubs.acs.org/doi/10.1021/... from Biogen

AlphaFold 3 prediction of the binding interface between SQSTM1/p62 and SHKBP1

Lin Luan

Xiaofu Cao

Our latest story: a protein-protein interaction between an E3 ubiquitin ligase and an autophagy adaptor affects liquid-liquid phase separation and sequestration of a key mediator of antioxidant signaling — but not via ubiquitination! Bravo to Lin Luan and Xiaofu Cao!
doi.org/10.1101/2025...

CDC's Morbidity and Mortality Weekly Report (MMWR) has provided real-time data and analysis about disease outbreaks and emerging health threats without a break every week since 1960.

Until today.

Distinct Classes of Gut Bacterial Molybdenum-Dependent Enzymes Produce Urolithins https://www.biorxiv.org/content/10.1101/2025.01.17.632430v1

Photo of David Lynch. Text: David Lynch, 1946-2025

BREAKING: David Lynch, the visionary filmmaker behind "Blue Velvet," "Twin Peaks" and "Mulholland Drive," has died at 78. apnews.com/article/davi...

Catalytic degradation of circulating targets with FcRn-mediated cycling LYTACs Circulating proteins are common targets for the discovery of occupancy-based inhibitors including monoclonal antibodies. Effective inhibition of target pathogenicity with blocking approaches, however,...

The unique pharmacology of targeted degraders (eg PROTACs) leverages their sub-stoichiometric “catalytic” activity. Now ⁦‪Lycia Tx‬⁩ reports catalytic (cata)LYTACs for potent, durable extracellular #TPD, cleared IgE in NHPs, superior to omalizumab 👏

www.biorxiv.org/content/10.1...

"On a molecular level, our structural studies reveal that interdictors bind in a linkerless heterobifunctional manner to both the rRNA and the nascent peptide chain ... much the way a PROTAC can be modularly designed and constructed"

Engineering covalent small molecule–RNA complexes in living cells - Nature Chemical Biology Small-molecule ligands have been developed that covalently attach to their cognate RNA aptamers in vitro and in living cells. This strategy opens up new avenues for RNA imaging applications (for examp...

Engineering covalent small molecule–RNA complexes in living cells
www.nature.com/articles/s41...

"Our findings raise expectations for the development of covalent RNA drugs and contribute to the evolving field of RNA-based therapeutics."