Boosting Neuroprotection with Combined Small-Molecule Repositioned Medicines

Summary

Fort the last 4 years, Fundación Teófilo Hernando (FTH) is developping a program focusing the search of small-molecule repositioned medicines, acting on targets linked to the pathogenesis of neurodegenerative diseases (NDDs). As a result of such effort, medicines with activities on those targets have been identified through pharmacological screenings of medicines from FTH chemical library, in cell cultures expressing those targets. The hypothesis underlying the project is based an the excellent therapeutic results obtained with combined medicines in various chronic diseases such as cancer, cardiac failure, infecctions or the epilepsies. In this context, it is plausible that the combination of medicines acting on different but complementary pathogenic pathways, could boost neuroprotection in Alzheimer’s disease (AD) and other NDDs. Some examples of such combinations are provided.

Introduction

FTH was named after Teófilo Hernando to honor the memory of the pioneer of Spanish pharmacology. The Foundation was created in 1996. At present, about 50 professionals work in preclinical research (the present project), clinical trials (as a CRO, Contract Research Organization), training of young researchers in all phases of R+D of new medicines, and the promotion of humanities in medical education. Here, focus is made on the translational preclinical project on drug repositioning in the area of neuroprotection and neurodegenerative diseases (NDDs).

The hypothesis

The last 25 years have witnessed a drastic improvement in the therapy of multiple cancer diseases. This has been due to several factora but particularly notable has been the combination of chemotherapeutic medicines. Drug combinations have also been highly successful in several other chronic diseases such as infections, cardiac failure, major depression or the epilepsies. The hypothesis behind the present project rest in this therapeutic success: the combination of medicines acting on various pathogenic pathways leading to neuronal death, should boost neuroprotecion in Alzheimer’s disease (AD) and other NDDs, as they share various of the pathogenic targets here explored.

The targets

Distorted calcium homeostasis, calcium-linked oxidative stress, and neuroinflammation are common pathogenic pathways of those NDDs. So, the FTH laboratory focus on ligands directed to those three pathogenic pathways: (1) blockers of voltage-dependent calcium channels of the L-subtype (Cav1.2); (2) blockers of the capacitative calcium entry channels (Orai1); (3) blockers of the calcium cannel of the purinergic receptor P2X7; (4) inducers of the transcription factor Nrf2; and (5) sequestration of free radicals.

Drug repositioning: the FTH chemical library

To shorten the pathway to success, FTH is seeking for neuroprotective properties of medicines that are already in clinical use for diseases and mechanisms other than those of NDDs. FTH chemical library has been built combining computational data mining, docking, and molecular dynamics approaches from large data bases, with pharmacological search of drugs mechanisms of action. So, about 300 medicines in clinical use have been selected so far; the library is continuosly being refined and enriched.

Pharmacological screening

The medicines included in the library are initially studied for their eventual activities on one given target, out of the five mentioned above. This is done in cell lines expressing a given target and maintained in cell cultures.

Some compounds with promising activities

FTH researchers have found that some medicines in clinical use for several disorders, exhibit activity in some of the targets being explored. Table 1 shows 5 of those medicines that cross the blood-brain barrier (BBB) and act with efficacy on one of those targets. For confidentiality issues, only the reference number of the five medicines are provided.

Table 1. Selected medicines with pharmacological activities on the project targets.

^(a)Fold-augmentation of Nrf2 expression; ^(b) per cent blockade of calcium entry through the human P2X7 purinergic receptor; ^(c) oxidative stress, fold-increase of free radical sequestration in trolox equivalents (ORAC); ^(d) % blockade of Ca²⁺ entry throug the voltage-dependent calcium cannel Cav1.2 (neuronal L-subtype); ^(e) % blockade of Ca²⁺ entry through Orai1 capacitative Ca²⁺ entry channel.

Ongoing research

Ongoing research at FTH is aimed at the following objectives:

• To look for neuroprotective effects of individual medicines in neuronal cultures treated with stressors.
• Additive or synergistic neuroprotection elicited by combinations of two or three medicines acting on the targets so far explored.
• Searching of new medicines to refine and enrich the FTH chemical library, combining computational and pharmacological approaches.
• Optimizing the pharmacological profile and mechanism of action of neuroprotective drugs, either alone or in combination.

Next steps

Once a given drug triad is optimized for its neuroprotective effects and the underlying mechanism of action, the proof-of-concept will be established in models of neurodegeneration more complex than cell cultures, namely:

• Organotypic cultures from brains of mouse models of AD, PD, HD and ALS.
• Neuroprotection exerted by the triad, in comparison with single-drug administration, in transgenic mouse models of neurodegenerative diseases.
• Drug interactions in pharmacokinetics, assays, among the three drugs included in the triad, on in vitro and in vivo animal models.
• Drug interactions in phase I clinical trials, in voluntary humans.
• Phase II and (eventually) phase III clinical trials to look for neuroprotection (disease modification) in AD patients, with drug triads.

Looking for collaboration and/or support

FTH is looking for collaboration or financial support, to pursue the final steps of preclinical experiments and for clinical trials in AD patients.

By Arturo García-de-Diego, Fundación Teófilo Hernando, Madrid, Spain. Email arturo.garcia@ifth.es