Assessing and improving specificity of rhodium metalloinstertors in targeting MMR deficient cancer

Abstract

Mismatch repair (MMR) deficiencies are a hallmark for 16% of all solid tumors and 80% of hereditary nonpolyposis colon cancers, and many patients with these types of malignancies are resistant to current oncol. treatments. Our lab. has conducted much work to develop mols. able to target the mismatches that result from MMR deficient cancers selectively. By incorporating particularly wide, arom., ancillary ligands, our Rh complexes are able to detect thermodynamically destabilized mismatch sites via a binding mode known as metalloinsertion, in which the inserting ligand binds DNA via the minor groove and results in ejection of the destabilized mismatched base pairs. We hypothesize that the complex binding site is later recognized as a lesion by the DNA repair machinery, which ultimately induces cytotoxicity. Our lab. evaluates different metalloinsertor complexes by comparing their biol. effects on mismatch repair proficient and deficient human colorectal cancer cell lines (HCT116). Currently, our most promising Rh complex [Rh(phen)(chrysi)( 2-(Pyridine-2-yl)propan-2-ol)]^(2+) (Rh-PPO) involves a unique rhodium-oxygen bond coordination with a puckered 5,6-chrysenequinone diimine inserting ligand. The complex displays submicromolar potency and can significantly differentiate the biol. activity between MMR -proficient and -deficient cell lines. Research in the lab has focused on further assessing Rh-PPO's promise as a chemotherapeutic by conducting in vivo pharmacokinetic and efficacy studies within mice. These animal studies have given insight into the best tolerated dose levels and administration routes, the impact of Rh-PPO treatment on mouse survival, and the chem. stability of Rh-PPO in vivo. These efforts have further validated the potential use of Rh-PPO as a targeted therapeutic for MMR deficient cancers.