MEDSynth's research lines

Targeting human
Dihydroorotate Dehydrogenase (hDHODH)

Having already been validated as a therapeutic target for the treatment of autoimmune diseases, such as rheumatoid arthritis and multiple sclerosis, in the fall 2016 hDHODH has also been associated with acute myeloid leukemia (AML), a disease for which the standard of intensive care has not changed over the last four decades. The connection with AML opened up to totally new perspectives in the treatment of the disease as well as in the hDHODH field.

Since 2012, a
MEDSynth research line is dedicated to design innovative inhibitors of different DHODH isoforms (human and Plasmodium falciparum). Targeting the human isoform, by using innovative scaffold-hopping replacement techniques we were able to design compounds able to show in vitro brequinar-like hDHODH potency levels but superior activity in terms of cytotoxicity and immunosuppression on AML cell lines. Our best example was able to restore myeloid differentiation in leukemia cell lines at one-digit lower concentrations than those achieved in experiments with brequinar.
We are now at a late stage of
in vivo evaluation of our lead compound, close to clinical trials AML.

During the COVID-19 pandemic, the search for new molecular targets included hDHODH on the list of best treatment options to test against SARS-CoV-2. In March 2020, hDHODH inhibitors were validated to exert a double action both in fighting the replication of the virus and in reducing the inflammatory states associated with COVID-19 infections, the so-called cytokine storm.
In May 2020, our most promising
hDHODH inhibitor was found to possess potent anti-SARS-CoV-2 activity, associated with an optimal SI.

Targeting Plasmodium falciparum Dihydroorotate Dehydrogenase (PfDHODH)

Malaria is one of the three most impacting infectious diseases in the world (HIV/AIDS, tuberculosis and malaria) and kills millions of people every year.
The absence of effective vaccines and drug resistance for nearly all known antimalarial agents has compromised the efficacy of control programs.
Plasmodium falciparum Dihydroorotate Dehydrogenase (PfDHODH) is a clinically validated target for antimalarial drug development.
This line of research led us to develop compounds capable of selectively inhibiting
Pf-DHODH, rather than, its human counterpart in the microMolar range.

This project involves important collaboration with international laboratories such as
San Andreas University at La Paz (Bolivia), where activity on parasite is studied, and Nirma University at Ahmedabad (India), where in vivo tests could be performed.

Targeting Aldo Keto Reductase 1C3 (AKR1C3) for Prostate Cancer (PC) treatment

Prostate Cancer (PC) is the most common diagnosed tumour affecting men. A fatal metastatic form is castration-resistant prostate cancer (CRPC), caused by the reactivation of the androgen axis in androgen-deprived patients.
The enzyme
aldo-keto reductase 1C3 (AKR1C3) plays a central role in androgen biosynthesis in prostate tissue and is overexpressed in CRPC, therefore this enzyme has been investigated as an attractive therapeutic target for this disease.
non-steroidal anti-inflammatory drugs, such as flufenamic acid (FLU) and indomethacin, are known to inhibit AKR1C3 in micromolar range, although unselectively toward the other isoforms, C1 and C2, as well as cyclooxygenases (COX). Starting from the structures of these drugs, we applied bioisosteric techniques to design a new class of AKR1C3 inhibitors, potent, selective towards the C2 isoform but above all devoid of COX activity. Our lead compound was found to be highly selective (up to 450 times) toward AKR1C3 rather then the other isoforms, with minimal effects toward COX1 and COX2.

Targeting Gaba neurotransmission for the treatment of neurodegenerative pathologies

In GABAergic neurotransmission, GABA activates GABAa receptors (GABAAR) belonging to the ligand-dependent ion channel family. The high degree of structural heterogeneity of GABAARs, which sees them in multiple receptor subtypes constructed as pentamical groups composed of 19 different GABAAR subunits, is reflected in a rich and complex pharmacology based not only on the different subtypes but also on allosteric binding sites and different subcellular and regional localization. The absence of crystallographic coordinates has led to an intense use of bioisostery for the development of ligands (agonists or antagonists), selective for the different GABAAR subclasses and subtypes.

In collaboration with Prof. Bente Frolund's group at the University of Copenhagen for many years we have a research line aimed at developing GABA analogues. In many of our projects we have successfully used the hydroxytriazole system as an isoster of the carboxyl group, further functionalized in order to increase the binding with the active site.