ArticleProceedings of the National Academy of Sciences of the United States of America2002
Inhibitors of Ras/Raf-1 interaction identified by two-hybrid screening revert Ras-dependent transformation phenotypes in human cancer cells.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2002. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 54 papers.
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Who cites it
54 citing papers in PubMed, 143 citations in OpenAlex.
- Small-molecule RAS/RAF inhibitors target RAS-driven cancers via allosteric RAF disruption.Nature communications · 2026Article
- Real-Time Visualization of Isoform-Specific RAF-KRAS Interactions in Living Cells Using FRET-BRET Hybrid Biosensors.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Article
- Cancer research is not correlated with driver gene mutation burdens.Med (New York, N.Y.) · 2024Article
- The Abundance of KRAS and RAS Gene Mutations in Cancer.Methods in molecular biology (Clifton, N.J.) · 2024Article
- Targeting CRAF kinase in anti-cancer therapy: progress and opportunities.Molecular cancer · 2023Review
- Targeting the YAP-TEAD interaction interface for therapeutic intervention in glioblastoma.Journal of neuro-oncology · 2021Article
- Small molecule inhibitors of RAS proteins with oncogenic mutations.Cancer metastasis reviews · 2020Review
- Therapeutic targeting of RAS: New hope for drugging the "undruggable".Biochimica et biophysica acta. Molecular cell research · 2020Review
- Review
- Biology, pathology, and therapeutic targeting of RAS.Advances in cancer research · 2020Review
- Exploiting RAS Nucleotide Cycling as a Strategy for Drugging RAS-Driven Cancers.International journal of molecular sciences · 2019Review
- From basic researches to new achievements in therapeutic strategies of KRAS-driven cancers.Cancer biology & medicine · 2019Article
- Pharmacological targeting of RAS: Recent success with direct inhibitors.Pharmacological research · 2019Review
- Efforts to Develop KRAS Inhibitors.Cold Spring Harbor perspectives in medicine · 2018Review
- Article
- A multiplex preclinical model for adenoid cystic carcinoma of the salivary gland identifies regorafenib as a potential therapeutic drug.Scientific reports · 2017Article
- An engineered protein antagonist of K-Ras/B-Raf interaction.Scientific reports · 2017Article
- Total Chemical Synthesis and Folding of All-l and All-d Variants of Oncogenic KRas(G12V).Journal of the American Chemical Society · 2017Article
- The RAS-Effector Interaction as a Drug Target.Cancer research · 2017Review
- Specific blockade of Rictor-mTOR association inhibits mTORC2 activity and is cytotoxic in glioblastoma.PloS one · 2017Article
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Authors and funding
18 authors at 4 institutions in 3 countries.
Funding
Abstract
The interaction of activated Ras with Raf initiates signaling cascades that contribute to a significant percentage of human tumors, suggesting that agents that specifically disrupt this interaction might have desirable chemotherapeutic properties. We used a subtractive forward two-hybrid approach to identify small molecule compounds that block the interaction of Ras with Raf. These compounds (MCP1 and its derivatives, 53 and 110) reduced serum-induced transcriptional activation of serum response element as well as Ras-induced transcription by way of the AP-1 site. They also inhibited Ras-induced Raf-1 activation in human embryonic kidney 293 cells, Raf-1 and mitogen-activated protein kinase kinase 1 activities in HT1080 fibrosarcoma cells, and epidermal growth factor-induced Raf-1 activation in A549 lung carcinoma cells. The MCP compounds caused reversion of ras-transformed phenotypes including morphology, in vitro invasiveness, and anchorage-independent growth of HT1080 cells. Decreased level of matrix metalloproteinases was also observed. Further characterization showed that MCP compounds restore actin stress fibers and cause flat reversion in NIH 3T3 cells transformed with H-Ras (V12) but not in NIH 3T3 cells transformed with constitutively active Raf-1 (RafDeltaN). Finally, we show that MCP compounds inhibit anchorage-independent growth of A549 and PANC-1 cells harboring K-ras mutation. Furthermore, MCP110 caused G(1) enrichment of A549 cells with the decrease of cyclin D level. These results highlight potent and specific effects of MCP compounds on cancer cells with intrinsic Ras activation.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.