Discovery of a dual WDR5 and Ikaros PROTAC degrader as an anti-cancer therapeutic.
Journal
Oncogene
ISSN: 1476-5594
Titre abrégé: Oncogene
Pays: England
ID NLM: 8711562
Informations de publication
Date de publication:
06 2022
06 2022
Historique:
received:
21
12
2021
accepted:
27
04
2022
revised:
26
04
2022
pubmed:
8
5
2022
medline:
15
6
2022
entrez:
7
5
2022
Statut:
ppublish
Résumé
WD repeat domain 5 (WDR5), an integral component of the MLL/KMT2A lysine methyltransferase complex, is critically involved in oncogenesis and represents an attractive onco-target. Inhibitors targeting protein-protein interactions (PPIs) between WDR5 and its binding partners, however, do not inhibit all of WDR5-mediated oncogenic functions and exert rather limited antitumor effects. Here, we report a cereblon (CRBN)-recruiting proteolysis targeting chimera (PROTAC) of WDR5, MS40, which selectively degrades WDR5 and the well-established neo-substrates of immunomodulatory drugs (IMiDs):CRBN, the Ikaros zinc finger (IKZF) transcription factors IKZF1 and IKZF3. MS40-induced WDR5 degradation caused disassociation of the MLL/KMT2A complex off chromatin, resulting in decreased H3K4me2. Transcriptomic profiling revealed that targets of both WDR5 and IMiDs:CRBN were significantly repressed by treatment of MS40. In MLL-rearranged leukemias, which exhibit IKZF1 high expression and dependency, co-suppression of WDR5 and Ikaros by MS40 is superior in suppressing oncogenesis to the WDR5 PPI inhibitor, to MS40's non-PROTAC analog controls (MS40N1 and MS40N2, which do not bind CRBN and WDR5, respectively), and to a matched VHL-based WDR5 PROTAC (MS169, which degrades WDR5 but not Ikaros). MS40 suppressed the growth of primary leukemia patient cells in vitro and patient-derived xenografts in vivo. Thus, dual degradation of WDR5 and Ikaros is a promising anti-cancer strategy.
Identifiants
pubmed: 35525905
doi: 10.1038/s41388-022-02340-8
pii: 10.1038/s41388-022-02340-8
pmc: PMC9189076
mid: NIHMS1805493
doi:
Substances chimiques
Adaptor Proteins, Signal Transducing
0
Antineoplastic Agents
0
Ikaros Transcription Factor
148971-36-2
IKZF1 protein, human
0
Intracellular Signaling Peptides and Proteins
0
Ubiquitin-Protein Ligases
EC 2.3.2.27
WDR5 protein, human
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
3328-3340Subventions
Organisme : NCI NIH HHS
ID : R01 CA211336
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA268384
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA236209
Pays : United States
Organisme : NIGMS NIH HHS
ID : R01 GM122749
Pays : United States
Organisme : NIGMS NIH HHS
ID : P20 GM121293
Pays : United States
Organisme : NCI NIH HHS
ID : U54 CA217297
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA215284
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA262903
Pays : United States
Organisme : NIH HHS
ID : S10 OD028504
Pays : United States
Organisme : NCI NIH HHS
ID : P30 CA016086
Pays : United States
Organisme : NIGMS NIH HHS
ID : P20 GM103429
Pays : United States
Organisme : NIGMS NIH HHS
ID : R01 GM137009
Pays : United States
Organisme : NIH HHS
ID : S10 OD025132
Pays : United States
Organisme : NIGMS NIH HHS
ID : R35 GM131780
Pays : United States
Organisme : NCI NIH HHS
ID : P30 CA196521
Pays : United States
Organisme : NIGMS NIH HHS
ID : R24 GM137786
Pays : United States
Organisme : NIH HHS
ID : S10 OD018445
Pays : United States
Informations de copyright
© 2022. The Author(s), under exclusive licence to Springer Nature Limited.
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