DUALITY · An Integrated Computational and Experimental Approach to Rapid Synthesis of Highly Selective Dual-Targeted HDAC/CK2, MMP2/CK2 Inhibitors

An Integrated Computational and Experimental Approach to Rapid Synthesis of Highly Selective Dual-Targeted HDAC/CK2, MMP2/CK2 Inhibitors

Cancer is one of the most important health problems facing our society. It is the second leading cause of death worldwide and was responsible for an estimated 9.6 million deaths in 2018. (https://www.who.int/cancer/PRGlobocanFinal.pdf). Approximately 1 in 6 deaths worldwide are caused by cancer, according to the WHO report (https://gco.iarc.fr/). Given the complexity of this multifactorial disease, single-target drugs do not achieve satisfactory therapeutic effects. Conversely, drugs directed to more than one target may be clinically advantageous, making multi-target drugs an emerging area of increasing interest to the drug discovery community. This is a working track that we have chosen for this research work. The targets selected for the discovery of new anticancer drugs are three enzymes involved in the proliferation of tumor processes, namely protein kinase 2 (CK2), Histone deacetylase type1 (HDAC1), and matrix metalloproteinases (MMPs). Histone deacetylases (HDACs) are a family of epigenetic enzymes that remove acetyl groups from lysine on histones and other proteins. HDAC1 is overexpressed in different human cancers and is regarded as a promising drug target for cancer therapy. Matrix metalloproteinases (MMPs) are zinc-dependent peptidases involved in the remodeling of the extracellular matrix (ECM). Mammalian MMPs are classified into six subfamilies, one of them (gelatinases) constituted by MMP2 and MMP9. MMP2 has been associated with several pathologies and especially with cancer (https://www.doi.org/10.1039/c3ob41046c). Similarly, Matrix metalloproteinase-13 (MMP-13) slightly promotes tumor invasion and angiogenesis, although it has received the most attention because it is a central node in the cartilage degradation network The main objective of the project was the development of new multi-target single inhibitors, which might enhance drug efficacy and overcome the current pharmacokinetic limitations. Previous studies in the host group to obtain MMP2/CK2 dual inhibitors were unsuccessful. However, this study leads to the discovery of a series of highly potent MMP-13 inhibitors. These compounds have utility not only in cancer but mainly in osteoarthritis, which is the single most common cause of disability in older adults in Europe. During the secondment, the researcher studied the drug/ligand interactions of these new interesting inhibitors, using several physicochemical techniques, such as Nuclear Magnetic Resonance (NMR) spectroscopy techniques (Saturation transfer difference (STD and waterLOGSY), Isothermal Titration Calorimetry (ITC), and Surface Plasmon Resonance (SPR) techniques. A second objective in the project was to conjugate our inhibitors with another moiety capable of binding tumor over-expressed receptors improving their selectivity. After a bibliographic search, this objective was derived from the design of Proteolysis Targeting Chimeras (PROTACS). In this strategy, a protein-ligand is conjugated to a molecule capable of binding ligase (E3), which catalyzes the transfer of ubiquitin to a lysine residue of the target protein promoting its degradation. This technology provides a new attractive approach to drug design. It presents the advantages of being capable to modulate non-traditional drug targets and combat resistance mechanisms.

Текст от CORDIS, на английски · Данни: CORDIS, © Европейски съюз