Lead Optimization of Quinoline-Coumarin KRAS mRNA G-Quadruplex Ligands: Discovery of Non-Quaternary Ammonium Analogs as Translation Inhibitors.
KRAS mRNA G-quadruplexes (rG4s) in the 5'-untranslated region offer attractive targets for translational intervention in KRAS-driven cancers. We previously identified the quinoline-coumarin derivative 15a as a KRAS rG4 ligand that suppresses KRAS translation; however, its permanently charged quaternary ammonium center limits further optimization. Herein, we designed and synthesized a series of nonquaternary ammonium analogs to investigate whether this structural motif could be removed without compromising KRAS rG4-related activity. Q29 emerged as the most promising compound, showing high affinity for the KRAS rG4 and inhibiting KRAS translation. Q29 also exhibited potent antiproliferative activity across KRAS mutant cancer cells, improved cellular uptake and tolerability relative to 15a, and significant antitumor efficacy in a MIA PaCa-2 xenograft model. Collectively, our study establishes a viable strategy for optimizing KRAS rG4 ligands that retain activity despite removal of the permanent charge and identifies Q29 as a promising lead for further development of KRAS translation inhibitors.