Drugging an undruggable pocket on KRAS.
KRAS
NMR
fragment-based drug design
oncology
structure-based drug design
Journal
Proceedings of the National Academy of Sciences of the United States of America
ISSN: 1091-6490
Titre abrégé: Proc Natl Acad Sci U S A
Pays: United States
ID NLM: 7505876
Informations de publication
Date de publication:
06 08 2019
06 08 2019
Historique:
pubmed:
25
7
2019
medline:
27
3
2020
entrez:
24
7
2019
Statut:
ppublish
Résumé
The 3 human RAS genes, KRAS, NRAS, and HRAS, encode 4 different RAS proteins which belong to the protein family of small GTPases that function as binary molecular switches involved in cell signaling. Activating mutations in RAS are among the most common oncogenic drivers in human cancers, with KRAS being the most frequently mutated oncogene. Although KRAS is an excellent drug discovery target for many cancers, and despite decades of research, no therapeutic agent directly targeting RAS has been clinically approved. Using structure-based drug design, we have discovered BI-2852 (1), a KRAS inhibitor that binds with nanomolar affinity to a pocket, thus far perceived to be "undruggable," between switch I and II on RAS; 1 is mechanistically distinct from covalent KRAS
Identifiants
pubmed: 31332011
pii: 1904529116
doi: 10.1073/pnas.1904529116
pmc: PMC6689897
doi:
Substances chimiques
KRAS protein, human
0
Pharmaceutical Preparations
0
Guanosine Triphosphate
86-01-1
Proto-Oncogene Proteins p21(ras)
EC 3.6.5.2
Banques de données
PDB
['6GJ5', '6GJ6', '6GJ7', '6GJ8']
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.
Langues
eng
Sous-ensembles de citation
IM
Pagination
15823-15829Subventions
Organisme : NCI NIH HHS
ID : P50 CA095103
Pays : United States
Commentaires et corrections
Type : CommentIn
Type : CommentIn
Type : CommentIn
Informations de copyright
Copyright © 2019 the Author(s). Published by PNAS.
Déclaration de conflit d'intérêts
Conflict of interest statement: D.K., M.G., A.M., L.J.M., A.Z., M.M., A.G., D.C., S.F., T. Gerstberger, T. Gmashitz, P.G., D.H., W.H., J.H., J.K.-O., P.K., S.K., M.K., R.K., L.L., F.M., S.M.-M., C.P., J.R., C.S., Y.S., K.S., R.S., A.S., B.S., G.S., B.W., M.Z., M.P., and D.B.M. were employees of Boehringer Ingelheim at the time of this work.
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