Rohit Bhattacharjee, Amity University Kolkata
Acyl CoA synthetase 4 (ACSL4) is an isoenzyme of the fatty acid ligase-coenzyme A family that takes part in arachidonic acid metabolism and steroidogenesis. ACSL4 is involved in tumour aggressiveness in breast and prostate tumours through various signal transduction pathways regulation. A well-validated ACSL4 inhibitor, however, has not been reported that hinders the entire exploration of the promising target and its therapeutic application on cancer and steroidogenesis inhibition. But in this regard, PRGL493 is identified as a homology model for ACSL4 and docking based virtual screening. Then it was chemically characterized through NMR and mass spectroscopy.
The inhibitory activity was demonstrated through the inhibition of arachidonic acid transformation into arachidonoyl CoA using recombinant enzyme and cellular models. The compound blocked cell proliferation and tumour growth in both breast and prostate cellular and animal models and sensitized the tumour cells to chemotherapeutic and hormonal treatment. Additionally, PRGL493 inhibited de novo steroid synthesis in testis and adrenal cells, in a mouse model and prostate tumour cells. This work proves the concept for potential application of PRGL493 in clinical practice. Moreover, they might prove keys to therapies aiming at control of tumour growth and drug resistance in tumours that express Acyl CoA synthetase 4 (ACSL4) and rely on steroid synthesis.
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Source-
Castillo, A.F., Orlando, U.D., Maloberti, P.M. et al. New inhibitor targeting Acyl-CoA synthetase 4 reduces breast and prostate tumour growth, therapeutic resistance and steroidogenesis. Cell. Mol. Life Sci. (2020). https://doi.org/10.1007/s00018-020-03679-5
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