@nckvalerie
Assistant Professor @ Karolinska Institutet, Stockholm, Sweden | Interested in understanding drug action π and simplifying complex biology π¬. Cancer biology and metabolism | DNA repair | drug discovery | next-gen chemical biology | https://t.ly/uzrfe
A near-complete map of human cytosolic degrons and their relevance for disease
We measured degron potency of >200,000 30-residue tiles from >5,000 human proteins, and trained a model to predict degrons from sequence
Led by @vvouts.bsky.social in @rhp-lab.bsky.social
doi.org/10.1126/scia...
Blog post: Just quit
Quitting projects in science is hard, but we should be doing a lot more of it.
open.substack.com/pub/arjunraj...
A modular lentiviral system for multiplexed gene perturbation and functional analysis reveals interdependence of hormone receptors in breast cancer growth in vivo https://www.biorxiv.org/content/10.64898/2025.12.07.692832v1
Researchers have performed a large-scale genetic screen to uncover the hidden roles of #microproteins. One of the discovered microproteins, named PIPPI, was found to protect cells from stress in the endoplasmic reticulum. Published in @narjournal.bsky.social π§ͺ #proteomics news.ki.se/new-micropro...
Also thanks to @ki.se, @scilifelab.se, @novonordisk.bsky.social, Cancerfonden, and Barncancerfonden for continued support.
#NUDT5 #metabolism #thiopurines #chemotherapy #cancer #biomarker #PROTACs #TPD
4/4
Our data complements recent works from the Yang, Kubicek/Huber, DeBerardinis, and Jourdain labs to position NUDT5 as a core regulator of nucleotide metabolism and rheostat of NA drug efficacy.
A huge thanks to the Altun lab, SciLifeLab DDDP, @seanrudd.bsky.social, and others.
3/n
We find that NUDT5-depleted cells are stuck in de novo purine biosynthesis (DNPB) with impaired nucleotide salvage. NUDT5 binds PPAT, the rate-limiting enzyme of DNPB, and appears to regulate its activity and PRPP availability to impair salvage-mediated NA drug activation.
2/n
Happy to share a new preprint on NUDT5's role in regulating nucleoside analog (NA) drug efficacy. π π
π§΅: We show that perturbing NUDT5 abundance by RNAi or a PROTAC (DDD2), but not inhibition with TH5427, desensitizes cells to thiopurines and most NA drugs in a titratable manner.
1/n
On the left - western blot of B16F10 cells wt and KO for CDK8. Our in house produced antibodies give a lot of unspecific bands. On the right same probes with antibodies preincubated with fixed CDK8 KO cells - there is a specific band and faint unspecific bands, which can be probably eliminated with increase of amount of KO cells.
Neat trick if you polycolonal ab's suck. Incubate them with fixed cells with a KO of your protein of interest, then spin. Protocol here: www.med.upenn.edu/markslab/ass...
I was amazed how well it worked on first try (I'm sure that I can completely eliminate unspecific bands)
#WesternBlot #cellsky
@mortusewicz.bsky.social
DNAi: an open-source AI tool for unbiased DNA fiber analysis https://www.biorxiv.org/content/10.1101/2025.09.30.679603v1
Congrats to first author, Seher Alam, and thanks to all students and collaborators!
We're grateful for support from @scilifelab.se, @novonordisk.bsky.social, and Cancer Research KI, as well as fellowships from Barncancerfonden and Cancerfonden.
Fin
#TPD #PROTAC #CeTEAM #NUDT5
β’ CeTEAM stability-dependent sensors for CRBN and VHL to monitor E3 ligase binding (and ternary complex "hook" effects) β
π
Oh yeah, and a functional VHL-directed NUDT5 PROTAC, DDD2, which complements a CRBN variant reported by @chembiohub.bsky.social.
More on NUDT5 coming soon, stay tuned!
3/4
Lots of cool TPD nuggets in this one:
β’ A modular, scalable cell-based degradation platform β
β’ Lysine-less FKBP12 F36V tag as a POI degradability handle β
β’ Lysine mapping reveals CRL4^CRBN accessibility limitations vs CRL2^VHL, which could have therapeutic implications β
2/4
π¨ Happy to finally share our first @biorxivpreprint.bsky.social on PROTACs and TPD with Mikael Altun and DDDP @scilifelab.se. π¨
We develop a suite of cell-based methods to assess degrader functionality and show this with new PROTACs toward NUDT5 as PoC.
π
www.biorxiv.org/content/10.1...
𧡠1/4
This phenomenon describes how those with an early advantage or success tend to accumulate over time
https://go.nature.com/45AJ1Ni
NAD+ Sensing by PARP7 Regulates the C/EBPΞ²-Dependent Transcription Program in Adipose Tissue In Vivo https://www.biorxiv.org/content/10.1101/2025.04.07.647692v1
Discovery of a VHL molecular glue degrader of GEMIN3 by Picowell RNA-seq https://www.biorxiv.org/content/10.1101/2025.03.19.644003v1
This direct-to-cell CeTEAM selectivity assay should facilitate the discovery of truly selective PARPi (as well as triaging of PARP trapping tendencies!).
Congrats to all authors, esp. Maria Pires and Seher Alam!
Funding: Cancerfonden and Barncancerfonden π
#PARP
#selectivity
#CeTEAM
3/3
Many interesting insights here, notably:
1. PARP1/2 binding potency highly correlates with trapping-like behavior (in agreement with inhibition being the primary driver) π,
2. AZD5305/saruparib is a damn good PARP1-selective inhibitor π,
3. Clues for finding next-gen, selective PARPi! ππ§
2/n
Happy to share that this work out of @ki.se and @scilifelab.se on PARPi selectivity profiling in cells using duplexed PARP1/2 CeTEAM biosensors is now in press at JBC!π
www.jbc.org/article/S002...
Short π§΅: 1/n
Adam Curtis Title Card: We Too Are Trapped In A System. Text over a background of a large office building
THREAD
This Is The Story Of The The Pernicious Rise of AI-Generated Papers and their Online Impact
An Incomplete History Told In The Voice of Documentarian Adam Curtis
1/31
Conventional chemotherapy: millions of cures, unresolved therapeutic index Article abstract In recent decades, millions of patients with cancer have been cured by chemotherapy alone. By βcureβ, we mean that patients with cancers that would be fatal if left untreated receive a time-limited course of chemotherapy and their cancer disappears, never to return. In an era when hundreds of thousands of cancer genomes have been sequenced, a remarkable fact persists: in most patients who have been cured, we still do not fully understand the mechanisms underlying the therapeutic index by which the tumour cells are killed, but normal cells are somehow spared. In contrast, in more recent years, patients with cancer have benefited from targeted therapies that usually do not cure but whose mechanisms of therapeutic index are, at least superficially, understood. In this Perspective, we will explore the various and sometimes contradictory models that have attempted to explain why chemotherapy can cure some patients with cancer, and what gaps in our understanding of the therapeutic index of chemotherapy remain to be filled. We will summarize principles which have benefited curative conventional chemotherapy regimens in the past, principles which might be deployed in constructing combinations that include modern targeted therapies.
Great perspective on the importance of conventional chemotherapy.
Despite many many decades of successful use, do we understand how these drugs work?
www.nature.com/articles/s41...
Thrilled to share a wonderful collaboration with Scott Armstrong, Florian Perner & Shellaina Gordon - exciting times ahead!
www.biorxiv.org/content/10.1...
Very happy to have been able to contribute to this amazing story! Check out the paper at Nature Communications and the 𧡠by @nckvalerie.bsky.social below π. We believe #CeTeam will be an invaluable tool for #drugdiscovery and #targetvalidation in #cells
π: www.nature.com/articles/s41...
Also be sure to check out our follow-up preprint where we comprehensively profile PARP inhibitor selectivity in cells using duplexed PARP1 and PARP2 CeTEAM drug biosensors.
π: www.biorxiv.org/content/10.1...
π¨ Stay tuned for more upcoming CeTEAM-related science! π¨
7/7
What started as a fun side project with the help of Brent Page and Mikael Altun back in 2016, has finally emerged as a cool approach to facilitate drug discovery and our understanding of how drugs work.
Congrats to all coauthors!
#science #research #innovation #newpublication #drugdiscovery
6/x
We then followed drug binding events and related phenotypic changes (or other readouts) to define potential on-target vs off-target effects, clarify drug mechanism-of-action, screen for potential binding molecules at scale, and detect drug-target engagement in live mice. 5/x
This was shown in principle with mutants of human MTH1, NUDT15, PARP1, OGG1, and DHFR. We also show that the pool of compatible mutations can conceivably be expanded by structural homology β exemplified by transfer of a PARP1 destabilizing mutation to PARP2. 4/x
Binding of a drug molecule typically stabilizes the target protein, but this can be difficult to detect in cells without additional perturbation. In effect, we modulate protein turnover dynamics to enable detection of binding events in unperturbed states with a simple readout of abundance. 3/x