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We demonstrated that PMC79 inhibits KRAS mutated kinase activity and is selective for KRAS mutations not affecting the KRAS wild-type protein. KRAS inhibition is not dependent on actin polymerization or on proteasome. Molecular docking analysis suggests that this effect might result from protein dynamics associated with the mutations. We demonstrated that low doses of PMC79 potentiate 5-fluorouracil anticancer effect. \u201cIn vivo\u201d PMC79 \u201cproof of concept\u201d showed that it reduces tumor growth in the CAM-xenograft model and induces necrosis of the tumor in the xenograft mice model. PMC79 is a promising new \u201cmagic bullet\u201d for CRCs harboring mutated KRAS.<\/jats:p>","DOI":"10.1101\/2023.08.09.552513","type":"posted-content","created":{"date-parts":[[2023,8,14]],"date-time":"2023-08-14T00:35:12Z","timestamp":1691973312000},"source":"Crossref","is-referenced-by-count":1,"title":["Shifting KRAS hotspot mutations inhibition paradigm in colorectal cancer"],"prefix":"10.64898","author":[{"given":"Ana Rita","family":"Br\u00e1s","sequence":"first","affiliation":[]},{"given":"Ana","family":"Lopes","sequence":"additional","affiliation":[]},{"given":"Nuno","family":"Mendes","sequence":"additional","affiliation":[]},{"given":"Paulo J.","family":"Costa","sequence":"additional","affiliation":[]},{"given":"Anabela","family":"Ferreira","sequence":"additional","affiliation":[]},{"given":"Sara","family":"Granja","sequence":"additional","affiliation":[]},{"given":"Ana Paula","family":"Silva","sequence":"additional","affiliation":[]},{"given":"Francisco","family":"Tortosa","sequence":"additional","affiliation":[]},{"given":"F\u00e1tima","family":"Baltazar","sequence":"additional","affiliation":[]},{"given":"F\u00e1tima","family":"G\u00e4rtner","sequence":"additional","affiliation":[]},{"given":"Maria Jo\u00e3o","family":"Sousa","sequence":"additional","affiliation":[]},{"given":"Andreia","family":"Valente","sequence":"additional","affiliation":[]},{"given":"Ana","family":"Preto","sequence":"additional","affiliation":[]}],"member":"54368","reference":[{"key":"2023081614500812000_2023.08.09.552513v1.1","unstructured":"Bos JL . 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