Deferasirox derivatives as inhibitors of Kallikrein-related peptidases associated to neurodegenerative diseases.

Abstract

Kallikrein-related peptidases are a family of serine proteases which loss of activity regulation has been particularly linked to neurodegenerative diseases. Moreover, iron overload is also a key process in some of these leading pathological conditions, particularly Alzheimer's disease. We identified for the first time Deferasirox, a well-known FDA-approved iron chelator (DFX) as an initial hit for kallikrein's (KLK) inhibition and propose here the design and synthesis of a small library of molecules using DFX as chemical scaffold. Resulting sub-series of compounds were evaluated against lead central nervous system KLK's, namely KLK1, KLK6 and KLK8 using targeted pharmacomodulations on DFX. Beyond DFX, several reversible micromolar inhibitors of these KLKs have been identified as hits and were shown to be devoid of any noticeable cytotoxicity towards neural cell lines commonly used in the field of neurodegenerative diseases. Their ability to chelate iron was also assessed in comparison to DFX and preformed iron-compound complexes displayed slightly improved inhibition potency for some derivatives with a KLK-dependent manner. Hence, we identified several DFX derivatives as promising starting points for the development of dual therapeutic agents in the context of neurodegenerative diseases where both deregulated KLK's proteolysis and iron dysregulation are involved.