From Kinase Inhibitors to Multitarget Ligands as Powerful Drug Leads for Alzheimer's Disease using Protein‐Templated Synthesis

Vanesa Nozal,Eva P Cuevas,Ana Martínez,Fernando Bartolomé,Concepción Pérez,Valle Palomo,David Ramírez,Alfonso García‐Rubia,Eva Carro,Carlota Tosat‐Bitrián

doi:10.1002/ange.202106295

Abstract

AbstractMultitarget directed ligands (MTDLs) are arising as promising tools to tackle complex diseases. The main goal of this work is to create powerful modulating agents for neurodegenerative disorders. To achieve this aim, we have combined fragments that inhibit key protein kinases involved in the main pathomolecular pathways of Alzheimer's disease (AD) such as tau aggregation, neuroinflammation and decreased neurogenesis, whilst looking for a third action in beta‐secretase (BACE1), responsible of β‐amyloid production. We obtained well‐balanced MTDLs with in vitro activity in three different relevant targets and efficacy in two cellular models of AD. Furthermore, computational studies confirmed how these compounds accommodate adequately into the long and rather narrow BACE1 catalytic site. Finally, we employed in situ click chemistry using BACE1 as protein template as a versatile synthetic tool that allowed us to obtain further MTDLs.

Highlights

The lack of effective treatments for severe diseases characterized by a multifactorial etiology or therapeutic resistances, such as neurodegenerative disorders, cancer or bacterial infections, has led to the emergence of a new drug design paradigm: the multitarget approach strategy.[1,2] Multitarget directed ligands (MTDLs) are characterized for showing activity in more than one molecular target taking advantage of multiple additive or synergic pharmacodynamic activities in a single molecule
The volume gained by linking two different protein kinase inhibitors could adjust into BACE1 catalytic site, which is able to accommodate eleven amino acid substrates (Figure 2 a).[22]
Our working hypothesis consisted in the use of the linkage design to build BACE1 inhibitors starting from kinase inhibitor fragments and obtaining MTDLs with both activities on the different Alzheimers disease (AD) hallmarks

Summary

Introduction

The lack of effective treatments for severe diseases characterized by a multifactorial etiology or therapeutic resistances, such as neurodegenerative disorders, cancer or bacterial infections, has led to the emergence of a new drug design paradigm: the multitarget approach strategy.[1,2] Multitarget directed ligands (MTDLs) are characterized for showing activity in more than one molecular target taking advantage of multiple additive or synergic pharmacodynamic activities in a single molecule. The volume gained by linking two different protein kinase inhibitors could adjust into BACE1 catalytic site, which is able to accommodate eleven amino acid substrates (Figure 2 a).[22] Inhibitors for this protease are normally large molecules able to maximize Chemie interactions in this cavity stabilizing the flexible loop on its Nterminal domain known as “the flap” through its Tyr and locking BACE1 in an inactive conformation.[23] The central binding pockets on the active site bind hydrophobic groups such as the ones found in peptidomimetic compounds based on substrate transition-state analogues[24] or other scaffolds like those showed in Figure 2 b, including verubecestat,[25] OM-003,[26] 5I3Y ligand[27] and 5V0N ligand.[28,29] The BACE1 pharmacophore of amidine compounds, the most advanced BACE1 inhibitors in clinical trials, highlights the importance of heteroaromatic rings linked through an amide bond to optimally occupy S1 and S3 pockets.[30] our working hypothesis consisted in the use of the linkage design to build BACE1 inhibitors starting from kinase inhibitor fragments and obtaining MTDLs with both activities on the different AD hallmarks. Different cellular assays have been used to confirm the polypharmacology and applicability of our MTDLs

Results and Discussion

Conflict of Interest

Martínez*