Amb motiu del tancament d'estiu, la validació de documents es reprendrà a partir del 28 d'agost de 2026. Disculpeu les molèsties.
Con motivo del cierre de verano, la validación de documentos se reanudará a partir del 28 de agosto de 2026. Disculpad las molestias
Due to the summer closure, document validation will resume starting August 28, 2026. We apologize for any inconvenience.

Files

254636.pdf (2.81 MB)

Document type

Article

Version

Published version

Publication date

2023-01-01

Publication license

cc-by (c) Abuasaker, B. et al., 2023
Please use this identifier to cite or link to this item: https://hdl.handle.net/2445/219122

α4-α5 helices on surface of KRAS can accommodate small compounds that increase KRAS signaling while inducing CRC cell death

Journal Title

Authors

Director/Tutor

Journal ISSN

Volume Title

Related resource

https://doi.org/10.3390/ijms24010748

Abstract

Abstract: 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 4- 5 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 4- 5 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. Keywords: colorectal cancer; KRAS; molecular dynamics; docking; allosteric pocket; calmodulin; small molecule inhibitors; RAF; ERK; AKT

Subject

Tumors, Genètica, Mutació (Biologia), Càncer colorectal

Subject (English)

Tumors, Genetics, Mutation (Biology), Colorectal cancer

Citation

Collections

Articles publicats en revistes (Biomedicina)

Citation

ABUASAKER, Baraa, et al. α4-α5 helices on surface of KRAS can accommodate small compounds that increase KRAS signaling while inducing CRC cell death. International Journal of Molecular Sciences. 2023. Vol. 24, num. 1, pags. 748. ISSN 1661-6596. [consulted: 15 of August of 2026]. Available at: https://hdl.handle.net/2445/219122

Export metadata

JSON - METS

Share record