Rhodium Complexes Targeting DNA Mismatches as a Basis for New Therapeutics in Cancers Deficient in Mismatch Repair

Area of Science:

• Medicinal Chemistry
• Cancer Biology
• Molecular Oncology

Background:

• Microsatellite instability (MSI) cancers, comprising up to 20% of solid tumors, exhibit chemotherapy resistance due to DNA mismatch repair (MMR) pathway deficiencies.
• Rhodium metalloinsertors selectively bind to DNA mismatches and demonstrate cytotoxicity in MSI cancer cells.

Purpose of the Study:

• To identify and characterize potent and selective rhodium-based compounds for targeting MSI cancers.
• To investigate the mechanism of action and therapeutic potential of the lead compound, [Rh(chrysi)(phen)(PPO)]²⁺ (RhPPO).

Main Methods:

• Synthesis and evaluation of rhodium complexes with varying coordination spheres (N∧O vs. N∧N).
• Comparative studies using MMR-deficient (HCT116O) and MMR-proficient (HCT116N) cell lines.
• Assessment of DNA damage response, DNA replication inhibition, and cell death mechanisms.
• Localization studies using a fluorescently tagged RhPPO conjugate.
• In vivo efficacy testing in a mouse xenograft model of MSI cancer.

Main Results:

• Rhodium complexes with N∧O coordination exhibited superior cell potency compared to N∧N-coordinated compounds.
• RhPPO was identified as the most potent and selective compound, preferentially inducing DNA damage response and cell death in MMR-deficient cells.
• RhPPO localized to nuclear DNA mismatches, causing double-strand breaks and inhibiting proliferation.
• RhPPO demonstrated significantly higher cell potency than platinum-based chemotherapeutics and showed promising antitumor activity in a preclinical MSI cancer model.

Conclusions:

• RhPPO is a novel DNA-targeted therapeutic agent with enhanced potency and selectivity for MSI cancers.
• DNA mismatches represent a viable and critical target for the development of new chemotherapeutics for MSI cancers.
• RhPPO offers a promising alternative to current platinum-based chemotherapy for MSI cancer treatment.