From Organometallic Anticancer Agent Development Towards an Understanding of Metal Complex-Protein Interactions

Title:

From Organometallic Anticancer Agent Development Towards an Understanding of Metal Complex-Protein Interactions

Schedule:

Date: 13^th December, 2023 (Wednesday)

Time:  5 - 6 pm (HKT)

Venue: Lecture Theatre P1, Chong Yuet Ming Chemistry Building

Speaker:

Prof. Christian Hartinger

School of Chemical Science

University of Auckland

Biography

Prof. Hartinger received his PhD in Chemistry in 2001 under the supervision of Bernhard Keppler at the University of Vienna. After a period at the University of Vienna, he joined Paul Dyson's group at the EPFL in Switzerland in 2006 as a Schrödinger Fellow. He returned to Vienna in 2009 to finish  his habilitation. In 2011, he accepted a position as Associate Professor at the University of Auckland and was promoted to Professor in 2016.   He  received national and international recognition with the Society of Biological Inorganic Chemistry Early Career Award 2016, the NZ Institute of Chemistry’s premier award, the Maurice Wilkins Centre Prize for Chemical Science, in 2016, the NZAS Hill Tinsley Medal in 2017, the Morrison Medal of the Australian and New Zealand Society for Mass Spectrometry in 2019, and he was elected a Fellow of the Royal Society of New Zealand in 2021, among others.

Abstract

The approaches taken to develop novel metal-based anticancer agents have considerably changed over the last 50 years since the discovery of the platinum drugs and focus now on compounds that interact with proteins overexpressed in tumor cells, show novel modes of DNA interactions or accumulate with higher selectivity in tumors, to name a few. Bioactive metal complexes are often considered promiscuous in their binding to proteins, in that they interact with a variety of proteins and a multitude of amino acids on a protein surface can be metallated. This confuscates the identification of specific interactions of relevance and bioactivity, as not all metalation events will contribute equally or may even be detrimental. The exception to this observation is the organometallic anticancer agent plecstatin-1, which was found to bind to plectin.[1]

In this contribution, I will discuss concepts we use in anticancer metallodrug design (Figure 1) and metallomics strategies to interrogate their modes of action. I will focus on the impact of ligand structures on the binding of their organometallic complexes to proteins,[2] which will be complemented by observations of unexpected reactions and surprising behavior in the presence of these biomolecules.[3] These studies lead us to develop an improved understanding of the driving forces for protein surface metalation and selectivity for some sites over others. Overall, it appears as a combination of parameters contributes to the selectivity of binding, including primary and secondary protein structures, steric demand of metal complex co-ligands and the presence of surface grooves with complementary features to those of the binding metal moieties that facilitate hydrophobic and/or electrostatic interactions.

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