New inhibitor targeting Acyl-CoA synthetase 4 reduces breast and prostate tumor growth, therapeutic resistance and steroidogenesis.
In this study, ACSL4 inhibitor PRGL493 was identified using a homology model for ACSL4 and docking based virtual screening. PRGL493 was then chemically characterized through nuclear magnetic resonance and mass spectroscopy. The inhibitory activity was demonstrated through the inhibition of arachidonic acid transformation into arachidonoyl-CoA using the recombinant enzyme and cellular models. The compound blocked cell proliferation and tumor growth in both breast and prostate cellular and animal models and sensitized tumor cells to chemotherapeutic and hormonal treatment. Moreover, PGRL493 inhibited de novo steroid synthesis in testis and adrenal cells, in a mouse model and in prostate tumor cells. This work provides proof of concept for the potential application of PGRL493 in clinical practice. Also, these findings may prove key to therapies aiming at the control of tumor growth and drug resistance in tumors which express ACSL4 and depend on steroid synthesis.
PMID: 33068124 [PubMed - as supplied by publisher]
Source: Cellular and Molecular Life Sciences : CMLS - Category: Cytology Authors: Castillo AF, Orlando UD, Maloberti PM, Prada JG, Dattilo MA, Solano AR, Bigi MM, Ríos Medrano MA, Torres MT, Indo S, Caroca G, Contreras HR, Marelli BE, Salinas FJ, Salvetti NR, Ortega HH, Lorenzano Menna P, Szajnman S, Gomez DE, Rodríguez JB, Podesta E Tags: Cell Mol Life Sci Source Type: research