Imidazo[1,2-a]pyridine Derivatives as Aldehyde Dehydrogenase Inhibitors: Novel Chemotypes to Target Glioblastoma Stem Cells

Abstract

Glioblastoma multiforme (GBM) is the deadliest form of brain tumor. It is known for its ability to escape the therapeutic options available to date thanks to the presence of a subset of cells endowed with stem-like properties and ability to resist to cytotoxic treatments. As the cytosolic enzyme aldehyde dehydrogenase 1A3 turns out to be overexpressed in these kinds of cells, playing a key role for their vitality, treatments targeting this enzyme may represent a successful strategy to fight GBM. In this work, we describe a novel class of imidazo­[1,2-a]­pyridine derivatives as aldehyde dehydrogenase 1A3 inhibitors, reporting the evidence of their significance as novel drug candidates for the treatment of GBM. Besides showing an interesting functional profile, in terms of activity against the target enzyme and selectivity toward highly homologous isoenzymes, representative examples of the series also showed a nanomolar to picomolar efficacy against patient-derived GBM stem-like cells, thus proving the concept that targeting aldehyde dehydrogenase might represent a novel and promising way to combat GBM by striking its ability to divide immortally.

A Selective Competitive Inhibitor of Aldehyde Dehydrogenase 1A3 Hinders Cancer Cell Growth, Invasiveness and Stemness In Vitro

“…In this conformation, the phenyl ring in position 6 of the nucleus establishes contacts with the protein backbone, with Van der Waals contacts and hydrophobic interactions with the residues G136, R139, W189, N469, A470, L471 and Y472 ( Figure 2 B,C). It is worth noting that this is the same binding-site occupied by the cyclohexene ring of the natural ligand retinoic acid, by phenyl group of GA11 and its derivatives, how recently highlighted in previous published data [ 27 , 28 , 40 ], ( Figure 3 A). All mentioned amino acids, excluded the Y472, are conserved in each of the 1A1, 1A2, and 1A3 isozymes, highlighting this enzymatic area as “stabilizing ligand binding site” in the whole members of the 1A subfamily.…”

“…The ALDH1A3 is a well-known characterizing gene of glioblastoma, and its role and its over expression is correlated with alterations in the glycolysis/gluconeogenesis pathway. ALDH1A3 has been highlighted as a promising target for cancer treatment [ 23 , 27 , 28 , 29 ] and is recognized as a CSC marker. CSCs abundance are correlated with chemoresistance to the classical chemotherapies and with invasiveness and, consequently, with high malignancy.…”

“…However, the compound is devoid of any selectivity among the different ALDH1A isoforms. Through a rational ligand optimization described elsewhere [ 27 , 29 ], we obtained a potent and selective inhibitor, namely NR6, able to inhibit selectively the ALDH1A3 isoform and to induce cell death, blocking invasiveness and reducing expression of CSC markers. Compared to the parent compounds, NR6 conserves the same heterocycle scaffold with the addition of a cyanide group in the meta position of the 6-phenyl ring.…”

“…Different active molecules are available with different chemical scaffolds (daidizin, disulfiram) and inhibitory mechanisms, but as of today, none of these are approved for a clinical use, due to the lack of selectivity against one ALDH isoenzyme over the other members [ 26 ]. Recently, a novel class of ALDH1 inhibitors bearing the imidazo[1,2- a ]pyridine scaffold has been described, showing significant cytotoxicity activity when tested against different glioblastoma cell lines [ 27 , 28 , 29 ]. As reported by literature, other enzyme oxidoreductase as the aldose ketose reductases (AKRs) are directly involved in the phase II of xenobiotic metabolism, with a scavenger role, and are considered as potential target for cancer therapy [ 30 , 31 , 32 , 33 , 34 ].…”

Curcumin-based-fluorescent probes targeting ALDH1A3 as a promising tool for glioblastoma precision surgery and early diagnosis

“…Considering the wellknown catalytic function of ALDHs, they are regarded as the key enzymes that can detoxify harmful aldehydes within the organism, and this could be the reason why so many cytotoxic antineoplastic molecules are inactivated by CSCs [24][25][26] . As a result, ALDH1A1 and ALDH1A3 may protect CSCs from antineoplastic molecules, their levels could represent a prognostic factor that could anticipate the chemotherapy efficacy and their inactivation could make the tumour cells susceptible to medical treatments [27][28][29] . Since CSCs started to be considered as one of the key mechanisms used by the tumour to evade chemotherapy and radiation treatment, researchers decided to focus their attention on finding a way to selectively target this cellular subpopulation, that could help improve alreadyexisting therapies and prevent the relapse of the tumour.…”