Discovery of NSD2-Degraders from Novel and Selective DEL Hits.

Autor: LegaardAndersson J; Nuevolution A/S / Amgen Research Copenhagen, Rønnegade 8, 2100, Copenhagen, Denmark., Christensen J; University of Copenhagen, Biotech Research & Innovation Centre (BRIC), Ole Maaløes Vej 5, 2200, Copenhagen, Denmark., Kleine-Kohlbrecher D; University of Copenhagen, Biotech Research & Innovation Centre (BRIC), Ole Maaløes Vej 5, 2200, Copenhagen, Denmark., Vacher Comet I; University of Copenhagen, Biotech Research & Innovation Centre (BRIC), Ole Maaløes Vej 5, 2200, Copenhagen, Denmark.; Bioorigin Aps, Ole Maaløes Vej 3, 2200, Copenhagen, Denmark., Fullerton Støier J; University of Copenhagen, Biotech Research & Innovation Centre (BRIC), Ole Maaløes Vej 5, 2200, Copenhagen, Denmark.; Bioorigin Aps, Ole Maaløes Vej 3, 2200, Copenhagen, Denmark., Antoku Y; University of Copenhagen, Biotech Research & Innovation Centre (BRIC), Ole Maaløes Vej 5, 2200, Copenhagen, Denmark., Poljak V; Nuevolution A/S / Amgen Research Copenhagen, Rønnegade 8, 2100, Copenhagen, Denmark., Moretti L; Nuevolution A/S / Amgen Research Copenhagen, Rønnegade 8, 2100, Copenhagen, Denmark., Dolberg J; Nuevolution A/S / Amgen Research Copenhagen, Rønnegade 8, 2100, Copenhagen, Denmark., Jacso T; Nuevolution A/S / Amgen Research Copenhagen, Rønnegade 8, 2100, Copenhagen, Denmark., Jensby Nielsen S; Nuevolution A/S / Amgen Research Copenhagen, Rønnegade 8, 2100, Copenhagen, Denmark., Nørregaard-Madsen M; Nuevolution A/S / Amgen Research Copenhagen, Rønnegade 8, 2100, Copenhagen, Denmark., Franch T; Nuevolution A/S / Amgen Research Copenhagen, Rønnegade 8, 2100, Copenhagen, Denmark., Helin K; University of Copenhagen, Biotech Research & Innovation Centre (BRIC), Ole Maaløes Vej 5, 2200, Copenhagen, Denmark.; The Institute of Cancer Research (ICR), 237 Fulham Road, London, SW3 6JB, UK., Cloos PAC; University of Copenhagen, Biotech Research & Innovation Centre (BRIC), Ole Maaløes Vej 5, 2200, Copenhagen, Denmark.; Bioorigin Aps, Ole Maaløes Vej 3, 2200, Copenhagen, Denmark.
Jazyk: angličtina
Zdroj: Chembiochem : a European journal of chemical biology [Chembiochem] 2023 Dec 14; Vol. 24 (24), pp. e202300515. Date of Electronic Publication: 2023 Oct 24.
DOI: 10.1002/cbic.202300515
Abstrakt: NSD2 is a histone methyltransferase predominantly catalyzing di-methylation of histone H3 on lysine K36. Increased NSD2 activity due to mutations or fusion-events affecting the gene encoding NSD2 is considered an oncogenic event and a driver in various cancers, including multiple myelomas carrying t(4;14) chromosomal translocations and acute lymphoblastic leukemia's expressing the hyperactive NSD2 mutant E1099 K. Using DNA-encoded libraries, we have identified small molecule ligands that selectively and potently bind to the PWWP1 domain of NSD2, inhibit NSD2 binding to H3K36me2-bearing nucleosomes, but do not inhibit the methyltransferase activity. The ligands were subsequently converted to selective VHL1-recruiting NSD2 degraders and by using one of the most efficacious degraders in cell lines, we show that it leads to NSD2 degradation, decrease in K3 K36me2 levels and inhibition of cell proliferation.
(© 2023 Wiley-VCH GmbH.)
Databáze: MEDLINE
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