# Computational Analysis of a Next-Generation Platinum-Based Chemotherapies that Induce DNA Double-Strand Breaks

## TL;DR

A new platinum-based drug, Aurkine16, shows promise in targeting cancer cells by causing DNA double-strand breaks without significant toxicity.

## Contribution

Aurkine16's unique activation pathway and DNA targeting mechanism are computationally analyzed, revealing its potential as a next-generation platinum-based therapy.

## Key findings

- Aurkine16 induces DNA double-strand breaks in both naïve and cisplatin-resistant cancer cells.
- Molecular dynamics simulations suggest Aurkine16 avoids off-target interactions in nucleosome cores.
- Aurkine16 forms stable [Aurki-GGG]3+ complexes and shows selectivity for cancer cells.

## Abstract

Platinum-based chemotherapeutic agents, such as cisplatin
(Cis-Pt­(II)),
are widely used in cancer treatment but are limited by toxicity, DNA
repair by cancer cells, and drug resistance. To address these limitations,
we designed and synthesized in our laboratories a novel platinum-based
compound, Aurkine16. In our previous studies, Aurkine16 demonstrated
outstanding therapeutic efficacy, selectively inducing double-strand
DNA breaks in both naïve and cisplatin-resistant cancer cells,
without detectable toxic side effects at clinically relevant doses.
In the present work, we report a computational analysis of Aurkine16,
which reveals its unique activation pathway and its capacity to form
stable [Aurki-GGG]3+ complexes. Unlike Cis-Pt­(II), which
induces single-strand DNA breaks, Aurkine16 simultaneously targets
multiple nucleic bases, causing double-strand breaks and significant
DNA disruption. Additionally, molecular dynamics simulations suggest
that Aurkine16 is likely to exhibit specificity for cancer cells,
avoiding off-target interactions within the nucleosome core. This
selectivity, attributed to the steric hindrance from histone tails,
underscores its potential for effectively targeting chromatin-accessible
cancer cells. These computational findings position Aurkine16 as a
promising alternative to platinum-based drugs, particularly for CisPt-resistant
cancers.