α4-α5 Helices on Surface of KRAS Can Accommodate Small Compounds That Increase KRAS Signaling While Inducing CRC Cell Death.
AKT
ERK
KRAS
RAF
allosteric pocket
calmodulin
colorectal cancer
docking
molecular dynamics
small molecule inhibitors
Journal
International journal of molecular sciences
ISSN: 1422-0067
Titre abrégé: Int J Mol Sci
Pays: Switzerland
ID NLM: 101092791
Informations de publication
Date de publication:
01 Jan 2023
01 Jan 2023
Historique:
received:
06
10
2022
revised:
28
12
2022
accepted:
29
12
2022
entrez:
8
1
2023
pubmed:
9
1
2023
medline:
11
1
2023
Statut:
epublish
Résumé
KRAS is the most frequently mutated oncogene associated with the genesis and progress of pancreatic, lung and colorectal (CRC) tumors. KRAS has always been considered as a therapeutic target in cancer but until now only two compounds that inhibit one specific KRAS mutation have been approved for clinical use. In this work, by molecular dynamics and a docking process, we describe a new compound (P14B) that stably binds to a druggable pocket near the α4-α5 helices of the allosteric domain of KRAS. This region had previously been identified as the binding site for calmodulin (CaM). Using surface plasmon resonance and pulldown analyses, we prove that P14B binds directly to oncogenic KRAS thus competing with CaM. Interestingly, P14B favors oncogenic KRAS interaction with BRAF and phosphorylated C-RAF, and increases downstream Ras signaling in CRC cells expressing oncogenic KRAS. The viability of these cells, but not that of the normal cells, is impaired by P14B treatment. These data support the significance of the α4-α5 helices region of KRAS in the regulation of oncogenic KRAS signaling, and demonstrate that drugs interacting with this site may destine CRC cells to death by increasing oncogenic KRAS downstream signaling.
Identifiants
pubmed: 36614192
pii: ijms24010748
doi: 10.3390/ijms24010748
pmc: PMC9821572
pii:
doi:
Substances chimiques
Proto-Oncogene Proteins p21(ras)
EC 3.6.5.2
Proto-Oncogene Proteins B-raf
EC 2.7.11.1
KRAS protein, human
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Subventions
Organisme : Ministerio de ciencia, Innovación y Universidades, SPAIN
ID : PID2019-105483RB-I00/AEI/10.13039/501100011033
Organisme : Ministry of Economy, Industry and Competitiveness
ID : SAF2016-76239-R
Organisme : Ministerio de Ciencia e Innovación, Spain
ID : PID2020-118768RJ-I00
Organisme : Government of Catalonia
ID : 2017SGR1033
Organisme : The Spanish Structures and Excellence María de Maeztu
ID : MDM-2017-0767
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