ArticleInternational journal of molecular sciences2023
α4-α5 Helices on Surface of KRAS Can Accommodate Small Compounds That Increase KRAS Signaling While Inducing CRC Cell Death.
Article in International journal of molecular sciences, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 5 papers.
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Who cites it
5 citing papers in PubMed, 4 citations in OpenAlex.
- In Silico and In Vitro Elucidation of the Inhibitory Mechanism of Chlorogenic Acid AgainstFood science & nutrition · 2026Article
- RAS mutations and colorectal cancer metabolism: a metabolomic analysis of tissue samples.BMC cancer · 2025Article
- CCR7 in esophageal squamous cell carcinoma: an identification from single-cell and bulk transcriptome sequencing.Discover oncology · 2025Article
- Discovery of Hit Compounds Targeting the P4 Allosteric Site of K-RAS, Identified through Ensemble-Based Virtual Screening.Journal of chemical information and modeling · 2023Article
- Advances in Molecular Research of Oncogenes.International journal of molecular sciences · 2023Article
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Authors and funding
11 authors at 2 institutions in 1 country.
Funding
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 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.
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Registered trials
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