Chemical Biology & drug discovery @Max Planck Dortmund | All things Ubiquitin and bifunctionals @Gersch Lab.
Niko Klink
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This work would not have been possible without my amazing co-first authors Dr. Sebastian Urban and Dr. Med. Johanna Seier and everyone in this highly interdisciplinary team from the @crc1430.bsky.social and beyond.
#Deubiquitinases (DUBs), key regulators of ubiquitin signaling, have been increasingly recognized for functions beyond rescuing substrate proteins from proteasomal degradation. Due to a lack of selective chemical tools within the DUB space, finding these functions has proven to be very challenging.
Taking these now to our Model Systems (PDAC and melanoma), not only shows highly selective degradation of USP7 by our PROTACs (criteria for matched pair fulfilled!), but also striking differences between inhibitor and degrader treated cells. These differences also occur in many phenotypic assays!
To enable their systematic discovery, we addressed this urgent need with matched chemical pairs of DUB inhibitor and #degraders by focusing on USP7 as a case study. By using potent and selective modulators, we aimed to dissect phenotypes induced by inhibitors and degraders of USP7 in solid cancers.
We introduce NK192, a potent USP7 inhibitor of the widely used hydroxypiperidine scaffold. Converting it through the available exit vector to a biotin probe showed proteome-wide highly selective binding to USP7, fulfilling our criteria for the inhibitor side of the matched chemical pairs.
After making a bunch of degraders (most not shown here), we arrive at NK250 and NK266 ("Kurt Cubane"), two highly potent USP7 degraders in HiBiT and immune-based assays. NK250, is a faster degrader which we could correlate to its ability to form a stable ternary complex between USP7 and VHL.
Really excited to share the first chapter of my PhD as a preprint titled: Targeted degradation of USP7 in solid cancer cells reveals disparate effects of deubiquitinase inhibition vs. acute protein depletion: www.biorxiv.org/content/10.1.... If that sounds interesting to you, small tweetorial below👇
Big thanks also to Dr. Bikash Adhikari and Prof. Elmar Wolf from @wolflab23.bsky.social, as well as Dr. @martinschwalm.bsky.social for bringing their expertise to this project, @imprs-lm.bsky.social from the MPI Dortmund for the excellent support and everyone else who contributed to the prokect!
