Aldehyde Dehydrogenase Inhibitors: the Challenge to Defeat Cancer Stem Cells

Cancer is made of a heterogeneous community of different cells governed by cooperative interactions. A small percentage of them, bearing stem-like properties, plays more than most a key role in tumour perpetuating and progression, being endowed with indefinite self-renewal ability and aberrant differentiation capacity. Differently from tumour bulk cells, cancer stem-like cells (CSCs) are able to resist to cytotoxic treatments commonly exploited to target rapidly dividing cells, as they are characterized by a slow mitotic activity possibly associated with a quiescent G0/G1 state. Hence, rather than being eradicated, CSCs turn out to be selected over the cancer bulk, being free to drive tumour relapse and mediate metastasis. Therefore, they represent the reference sub-population that should be brought into focus, as undermining self-renewal signaling pathways supporting their growth and residence in the stem state may represent an effective strategy to wipe out efficiently the whole tumour architecture. Indeed, experience gained in the management of different malignancies proof the concept that targeting cancer stem cells improve patient outcomes by preventing tumours recurrences, increasing chemotherapy efficacy and reversing chemotherapy resistance. [1] CSCs exhibit high levels of the cytoplasmic enzyme aldehyde dehydrogenase, ALDH. Besides being acknowledged as the distinctive hallmark of this type of cancer cell sub-population, ALDH plays also a crucial role in stem cells vitality, being involved in the differentiation of progenitor cells into mature entities. Its overexpression is also decisive for tumor invasion, thus having a prognostic value for poor clinical outcomes. Accordingly, targeting this enzyme might represent a successful strategy to put in place a keystone molecular treatment of cancer. [2] Here we present a series of imidazo[1,2-a]pyridine derivatives, developed as ALDH inhibitors. The novel compounds proved to block the catalytic activity of ALDH1A3 isoenzyme, showing high degrees of selectivity against the parent ALDH1A1 and ALDH1A2 subtypes. Tested in vitro on different populations of CSCs, including glioma and prostate cancer stem cells, the imidazo[1,2-a]pyridine derivatives displayed also a relevant anti-proliferative efficacy. Results obtained will be discussed