Functional characterization of a PROTAC directed against BRAF mutant V600E.
Animals
Female
Humans
Mice
Antineoplastic Agents
/ pharmacology
Apoptosis
/ drug effects
Cell Line, Tumor
Cell Proliferation
/ drug effects
Drug Design
Drug Resistance, Neoplasm
Extracellular Signal-Regulated MAP Kinases
/ metabolism
Gene Expression Regulation
MAP Kinase Signaling System
Mitogen-Activated Protein Kinase Kinases
/ metabolism
Models, Molecular
Molecular Structure
Molecular Targeted Therapy
Mutation
Phosphorylation
/ drug effects
Protein Binding
Protein Kinase Inhibitors
/ pharmacology
Proteolysis
Proto-Oncogene Proteins B-raf
/ antagonists & inhibitors
Signal Transduction
Structure-Activity Relationship
Thalidomide
/ analogs & derivatives
Ubiquitin
/ chemistry
Journal
Nature chemical biology
ISSN: 1552-4469
Titre abrégé: Nat Chem Biol
Pays: United States
ID NLM: 101231976
Informations de publication
Date de publication:
11 2020
11 2020
Historique:
received:
11
11
2019
accepted:
01
07
2020
pubmed:
12
8
2020
medline:
19
12
2020
entrez:
12
8
2020
Statut:
ppublish
Résumé
The RAF family kinases function in the RAS-ERK pathway to transmit signals from activated RAS to the downstream kinases MEK and ERK. This pathway regulates cell proliferation, differentiation and survival, enabling mutations in RAS and RAF to act as potent drivers of human cancers. Drugs targeting the prevalent oncogenic mutant BRAF(V600E) have shown great efficacy in the clinic, but long-term effectiveness is limited by resistance mechanisms that often exploit the dimerization-dependent process by which RAF kinases are activated. Here, we investigated a proteolysis-targeting chimera (PROTAC) approach to BRAF inhibition. The most effective PROTAC, termed P4B, displayed superior specificity and inhibitory properties relative to non-PROTAC controls in BRAF(V600E) cell lines. In addition, P4B displayed utility in cell lines harboring alternative BRAF mutations that impart resistance to conventional BRAF inhibitors. This work provides a proof of concept for a substitute to conventional chemical inhibition to therapeutically constrain oncogenic BRAF.
Identifiants
pubmed: 32778845
doi: 10.1038/s41589-020-0609-7
pii: 10.1038/s41589-020-0609-7
pmc: PMC7862923
mid: NIHMS1652685
doi:
Substances chimiques
Antineoplastic Agents
0
BRAF protein, human
EC 2.7.11.1
Extracellular Signal-Regulated MAP Kinases
EC 2.7.11.24
Mitogen-Activated Protein Kinase Kinases
EC 2.7.12.2
pomalidomide
D2UX06XLB5
Protein Kinase Inhibitors
0
Proto-Oncogene Proteins B-raf
EC 2.7.11.1
Thalidomide
4Z8R6ORS6L
Ubiquitin
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
1170-1178Subventions
Organisme : NCRR NIH HHS
ID : S10 RR029205
Pays : United States
Organisme : CIHR
ID : FDN 143343
Pays : Canada
Organisme : NIGMS NIH HHS
ID : P41 GM103403
Pays : United States
Organisme : CIHR
ID : FRN 414829
Pays : Canada
Organisme : NIGMS NIH HHS
ID : P30 GM124165
Pays : United States
Organisme : CIHR
ID : FDN 388023
Pays : Canada
Organisme : CIHR
ID : FDN 143277
Pays : Canada
Organisme : CIHR
ID : FDN 144301
Pays : Canada
Commentaires et corrections
Type : CommentIn
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