A Quadruple‐Action Platinum(IV) Prodrug with Anticancer Activity Against KRAS Mutated Cancer Cell Lines

Abstract

We developed a novel Pt^IV prodrug that simultaneously releases four different bioactive moieties inside the cancer cell. Its cytotoxicity against monolayer cultures (2D) and spheroid (3D) cancer cells is significantly better than cisplatin. It is 200-450-fold more potent than cisplatin against KRAS mutated pancreatic and colon cancers and is 40-fold more selective towards KRAS mutated cells compared to non-cancerous. This is important since RAS proteins play a role in regulating cell differentiation, proliferation, and survival and KRAS is mutated in 90 % of pancreatic adenocarcinomas, 45 % of colorectal cancers, and 35 % of lung adenocarcinomas. The selectivity index, determined by dividing the IC₅₀ value in non-cancerous cells by that of a cancerous cell line, is two-fold better than cisplatin, attesting to preferential cytotoxicity towards neoplastic cells.