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Non-G12C mutant inhibitors Non-G12C KRAS mutations, particularly G12D and G12V, are highly prevalent in PDAC and CRC and lack a cysteine residue for covalent targeting, necessitating alternative therapeutic strategies.46 MRTX1133 was the first non-covalent KRAS-G12D inhibitor (G12Di) discovered through structure-based design, binding both GDP-bound and GTP-bound states with ~700-fold selectivity over wild-type KRAS protein.47 In PDAC mouse models, it induced tumour regression and shifted tumours towards a classical phenotype, enhancing chemosensitivity.48 Although MRTX1133 advanced to a phase 1/2 trial (NCT05737706), the study was terminated in 2025 due to variable and suboptimal pharmacokinetics despite an acceptable safety profile

Mahmoud AM, Hussein OE, Abd El-Twab SM, Hozayen WG (2019) Ferulic acid protects against methotrexate nephrotoxicity via activation of Nrf2/ARE/HO-1 signaling and PPAR, and suppression of NF-B/NLRP3 inflammasome axis

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Dhalluin, C