Acquired and inherent tumor resistance and high systemic toxicity are the major drawbacks of current cancer chemotherapies.  Non-small cell lung cancer (NSCLC), for instance, is notoriously resistant to DNA-targeted therapies because the damage produced by these agents is sensed by cellular DNA repair mechanisms.  A new class of platinum�acridine agents has been identified that damage cellular DNA by a unique mechanism different from the typical cross-link formation by cisplatin and related clinical platinum-based chemotherapies.  The most active derivatives discovered to date show cancer cell kill in the low-nanomolar range in NSCLC cell lines, rendering these agents approximately 500-times more potent than cisplatin.  The lead compound of this class of compounds has demonstrated tumor growth inhibition in an NCI-H460 xenograft model in mice. This presentation summarizes recent insights into structure�activity relationships, DNA interactions, as well as critical pharmacological properties of the hybrid agents.  Classical prodrug concepts aimed at reducing the systemic toxicity of the hybrid agents are discussed.  In addition, novel technologies will be presented in which cytotoxic complexes have been functionalized with conjugatable groups to introduce them as �warhead� components in smarter therapies to target lung cancers with mutated EGFR and ER+ breast cancer.  Preliminary proof-of-principle biochemical and cellular studies will also be presented.  This work is supported by the National Institutes of Health (CA101880).

Engineering highly cytotoxic platinum-acridine agents into targeted therapies for chemoresistant cancers

243rd National Meeting (2012)

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