11PS04 is a new chemical entity identified by microRNA-based biosensing with promising therapeutic potential against cancer stem cells

Abstract

Phenotypic drug discovery must take advantage of the large amount of clinical data currently available. In this sense, the impact of microRNAs (miRs) on human disease and clinical therapeutic responses is becoming increasingly well documented. Accordingly, it might be possible to use miR-based signatures as phenotypic read-outs of pathological status, for example in cancer. Here, we propose to use the information accumulating regarding the biology of miRs from clinical research in the preclinical arena, adapting it to the use of miR biosensors in the earliest steps of drug screening. Thus, we have used an amperometric dual magnetosensor capable of monitoring a miR-21/miR-205 signature to screen for new drugs that restore these miRs to non-tumorigenic levels in cell models of breast cancer and glioblastoma. In this way we have been able to identify a new chemical entity, 11PS04 ((3a R ,7a S )-2-(3-propoxyphenyl)-7,7a-dihydro-3a H -pyrano[3,4- d ]oxazol-6(4 H )-one), the therapeutic potential of which was suggested in mechanistic assays of disease models, including 3D cell culture (oncospheres) and xenografts. These assays highlighted the potential of this compound to attack cancer stem cells, reducing the growth of breast and glioblastoma tumors in vivo . These data demonstrate the enhanced chain of translatability of this strategy, opening up new perspectives for drug-discovery pipelines and highlighting the potential of miR-based electro-analytical sensors as efficient tools in modern drug discovery.

MV1035 Overcomes Temozolomide Resistance in Patient-Derived Glioblastoma Stem Cell Lines

“…Cells were treated with concentrations of MV1035 (10, 25, and 50 µM) previously tested for their ability to inhibit ALKBH2 and different TMZ concentrations. Since several TMZ IC50s are reported in the literature against glioblastoma cells [ 31 , 32 ], we have decided to treat our cells with a wide range of concentrations (75, 150, 300, 600, 1200 µM), alone or in combination with MV1035, for 24 h.…”