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

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

• CeTEAM stability-dependent sensors for CRBN and VHL to monitor E3 ligase binding (and ternary complex "hook" effects) ✅ 👀

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:
• A modular, scalable cell-based degradation platform ✅
• Lysine-less FKBP12 F36V tag as a POI degradability handle ✅
• Lysine mapping reveals CRL4^CRBN accessibility limitations vs CRL2^VHL, which could have therapeutic implications ✅

2/4

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 🙏

#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) 📈,
2. AZD5305/saruparib is a damn good PARP1-selective inhibitor 💊,
3. Clues for finding next-gen, selective PARPi! 🔎🧐

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!👇

www.jbc.org/article/S002...

Short 🧵: 1/n

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.

🔗: www.biorxiv.org/content/10.1...

🚨 Stay tuned for more upcoming CeTEAM-related science! 🚨

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