Kusal Samarasinghe

TFIIH kinase CDK7 drives cell proliferation through a common core transcription factor network CDK7 kinase activity is found to control RNAPII transcription through a cohort of TFs that drive cell cycle and proliferation.

For our latest paper, we worked with SYROS Pharmaceuticals, the groups of Dylan Taatjes and Robin Dowell at CU Boulder, and @abhaykot.bsky.social. Junjie Feng in my lab determined the #cryoEM structure of the CDK7 inhibitor SY5609 bound to its target...
www.science.org/doi/10.1126/...

An allosteric cyclin E-CDK2 site mapped by paralog hopping with covalent probes - Nature Chemical Biology Development of a paralog-hopping approach leveraging chemical proteomic data on covalently liganded cysteines revealed an allosteric pocket shared by cysteine-containing and cysteine-less paralogous c...

An allosteric cyclin E-CDK2 site mapped by paralog hopping with covalent probes

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

Excited about programming biology via induced proximity? Then mark June 2026 in your calendar and consider participating in the GRC Conference on Induced Proximity Modalities and Therapeutics that I am co-organizing with @danetteldaniels.bsky.social
tinyurl.com/brtuffam

Exosome-based targeted delivery of NF-κB ameliorates age-related neuroinflammation in the aged mouse brain - Experimental & Molecular Medicine As we age, our bodies undergo changes that can lead to diseases like Alzheimer’s and Parkinson’s. A key factor in this process is inflammation in the brain, driven by a protein called NF-κB. Researche...

Exosome-based targeted delivery of NF-κB ameliorates age-related neuroinflammation in the aged mouse brain

www.nature.com/articles/s12...

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...

Our paper on computational design of chemically induced protein interactions is out in @natureportfolio.bsky.social. Big thanks to all co-authors, especially Anthony Marchand, Stephen Buckley and Bruno Correia!

t.co/vtYlhi8aQm

'Ubiquitin Lysine-Linkages' from the review 'Ubiquitin: a structural perspective' in Molecular Cell

New to #ubiquitin? Been with it for a while? Either way this review may be for you 🤩

Excited to share our review article in @molcell.bsky.social, diving deep into everything #ubiquitin
Read here 👉: kwnsfk27.r.eu-west-1.awstrack.me/L0/https:%2F...

@cellpress.bsky.social
@wehi-research.bsky.social

Protein production for cryoEM structure determination just got a lot cheaper - high resolution structure from half a plate of HEK cells with the "MIcro ISolation (MISO)" microfluidics-based approach. Congrats to the Brunner and Efremov labs in Brussels! www.biorxiv.org/content/10.1...

Molecular Glue Degraders at Inflection Point as Pharma Dives In Novartis, Biogen, Takeda and Novo Nordisk are all betting on advances in the molecular glue degraders space, collectively investing billions in hopes of treating cancer, Alzheimer’s disease, cardiomet...

www.biospace.com/drug-develop...

On the Hunt for the Histone Code In BriefIn the early 2000s before high resolution mass spectrometers were readily available, the Hunt lab developed many approaches to analyze histone modifications on low resolution instruments.

In the early 2000s, Don Hunt's lab at UVa started developing mass spec based approaches to characterize histone PTMs. I and others were fortunate to be at the right place at the right time back then. Read an account about those early days here.
www.mcponline.org/article/S153...

Targeting lysine acetylation readers and writers - Nature Reviews Drug Discovery Lysine acetylation is a post-translational modification on histones and other proteins that is catalysed by acetyltransferases (‘writers’) and mediates interactions with bromodomains and other ‘reader...

Nice review from Phil. Cole lab.

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

Synthetic GPCRs for programmable sensing and control of cell behaviour - Nature Modular synthetic G-protein-coupled receptors with nanobody-based ligand-recognition domains can be designed and used to programme transgene expression, real-time fluorescence or endogenous G-protein ...

PAGER: Alerts intracellular circuits about therapeutically relevant diverse primary messengers.
www.nature.com/articles/s41...

One amazing aspect of cryo-EM revolution is there are a bunch of giant E3 Ubiquitin ligase complexes that are mechanistically accessible- this seems cool from the Rapé lab

A modular platform for bioluminescent RNA tracking - Nature Communications Studying RNA dynamics in vivo often relies on fluorogenic approaches, but these can be hampered by factors such as limited sensitivity and sample autofluorescence. Here, the authors describe an ultras...

Cool new work from Jenn Prescher and coworkers @ucirvine.bsky.social, “RNA lantern” technology for bioluminescence imaging of RNA transcripts

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

Vaccines for cancer prevention: exploring opportunities and navigating challenges - Nature Reviews Drug Discovery Cancer-preventive vaccines can reduce cancer occurrence by inducing a specific immune response against tumours before they can fully develop. This Review discusses results from pioneering clinical stu...

Vaccines for cancer prevention

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

Targeting RNA-protein interactions with small molecules: promise and therapeutic potential - Medicinal Chemistry Research The therapeutic potential of targeting protein-RNA interactions has not been fully explored. While several approaches to block the interactions between various RNA and protein partners have been devel...

Targeting RNA-protein interactions with small molecules: promise and therapeutic potential

link.springer.com/article/10.1...

μMap-Interface: Temporal Photoproximity Labeling Identifies F11R as a Functional Member of the Transient Phagocytic Surfaceome Phagocytosis is usually carried out by professional phagocytic cells in the context of pathogen response or wound healing. The transient surface proteins that regulate phagocytosis pose a challenging ...

pubs.acs.org/doi/10.1021/...

Telomere function and regulation from mouse models to human ageing and disease - Nature Reviews Molecular Cell Biology Telomere dysfunction, usually owing to shortening, activates cellular senescence and can contribute to age-associated diseases and cancer. Mouse models are crucial for telomere research, but human and...

Telomere function and regulation from mouse models to human ageing and disease

go.nature.com/3D2Cu1m

The redox sensor KEAP1 facilitates adaptation of T cells to chronic antigen stimulation by preventing hyperactivation KEAP1 promotes persistent T cell immunity and a stem-like T cell response during chronic antigen stimulation by repressing NRF2.

www.science.org/doi/10.1126/...

Medicinal Chemistry Education and Training OR SEARCH CITATIONS

Written by Craig Lindsley:
pubs.acs.org/doi/10.1021/...

PROTACs are revolutionizing small molecule drug ​​development PROTACs are driving small molecule drug development to treat cancer, neurodegenerative diseases and more

Very nice overview of the PROTAC concept and its applications:
www.cas.org/resources/ca...

Critical assessment of LC3/GABARAP ligands used for degrader development and ligandability of LC3/GABARAP binding pockets - Nature Communications Autophagosome tethering compounds (ATTECs) are small molecule degraders hijacking the autophagy system. Here, the authors show that current ATTEC ligands did not bind to their designated targets but e...

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

Targeted Protein Degradation • From Small Molecules To Complex Organelles Our Special Research Program is a collaborative research platform to unravel how proteins are targeted for degradation.

www.protein-degradation.org/symposium/

Discovery of CRBN-Dependent WEE1 Molecular Glue Degraders from a Multicomponent Combinatorial Library Small molecules promoting protein–protein interactions produce a range of therapeutic outcomes. Molecular glue degraders exemplify this concept due to their compact drug-like structures and ability to...

pubs.acs.org/doi/10.1021/...

Allosteric activation of the SPRTN protease by ubiquitin maintains genome stability https://www.biorxiv.org/content/10.1101/2024.11.26.625192v1 The DNA-dependent protease SPRTN maintains genome stability by degrading toxic DNA-protein crosslink

Allosteric activation of the SPRTN protease by ubiquitin maintains genome stability https://www.biorxiv.org/content/10.1101/2024.11.26.625192v1

An engineered cereblon optimized for high throughput screening and molecular glue discovery Due to challenges in studying molecular interactions of CRBN, identification of CRBN based molecular glues has remained underexplored. Here, Bailey et al designed an easy-to-handle CRBN construct and ...

www.cell.com/cell-chemica...

Circular Engineered Sortase for Interrogating Histone H3 in Chromatin Reversible modification of the histone H3 N-terminal tail is critical in regulating the chromatin structure, gene expression, and cell states, while its dysregulation contributes to disease pathogenesis. Understanding the crosstalk between H3 tail modifications in nucleosomes constitutes a central challenge in epigenetics. Here, we describe an engineered sortase transpeptidase, cW11, that displays highly favorable properties for introducing scarless H3 tails onto nucleosomes. This approach significantly accelerates the production of both symmetrically and asymmetrically modified nucleosomes. We demonstrate the utility of asymmetrically modified nucleosomes produced in this way in dissecting the impact of multiple modifications on eraser enzyme processing and molecular recognition by a reader protein. Moreover, we show that cW11 sortase is very effective at cutting and tagging histone H3 tails from endogenous histones, facilitating multiplex “cut-and-paste” middle-down proteomics with tandem mass tags. This cut-and-paste proteomics approach permits the quantitative analysis of histone H3 modification crosstalk after treatment with different histone deacetylase inhibitors. We propose that these chemoenzymatic tail isolation and modification strategies made possible with cW11 sortase will broadly power epigenetic discovery and therapeutic development.

A great collaboration with Phil Cole (Harvard) engineering Sortase to facilitate its transpeptidase activity on histone H3 has been published in JACS. This work developed multiplexed "cut-and-paste" middle-down proteomics with tandem mass tags for quantification.
pubs.acs.org/doi/full/10....

Solution structure and synaptic analyses reveal determinants of bispecific T cell engager potency Bispecific T-cell engagers (TcEs) link T cell receptors to tumor-associated antigens on cancer cells, forming cytotoxic immunological synapses (IS). Close membrane-to-membrane contact (≤13 nm) has bee...

Cool preprint by ⁦Dustin and coworkers on how various T cell engager formats, w/varying geometries/rigidities, impact synapse structure and potency

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

An Activity-Based Sensing Approach to Multiplex Mapping of Labile Copper Pools by Stimulated Raman Scattering Molecular imaging with analyte-responsive probes offers a powerful chemical approach to studying biological processes. Many reagents for bioimaging employ a fluorescence readout, but the relatively br...

First Princeton paper! Activity-based sensing plus narrow Raman signatures enable multiplex copper imaging, revealing crosstalk between high antioxidant response element NRF2 activation and low labile Cu in cancer. Fun project with Wei Min’s lab at Columbia! #chemsky pubs.acs.org/doi/10.1021/...

TEAD-targeting small molecules induce a cofactor switch to regulate the Hippo pathway TEAD proteins are the main transcriptional effectors of the Hippo signaling pathway and a pharmacological target in oncology. Most TEAD-targeting small molecules act by disrupting interaction with the...

A Molecular glue promotes TEAD interaction with the transcriptional repressor VGLL4 to induce a small molecule-mediated cofactor switch from YAP to VGLL4 leading to counteract YAP activity at chromatin level to repress pro-growth gene networks.
www.biorxiv.org/content/10.1...