BRD4 PROTAC as a novel therapeutic approach for the treatment of vemurafenib resistant melanoma: Preformulation studies, formulation development and in vitro evaluation

European Journal of Pharmaceutical Sciences : Official Journal of the European Federation for Pharmaceutical Sciences
Drishti RathodKetan Patel

Abstract

Limited therapeutic interventions and development of resistance to targeted therapy within few months of therapy pose a great challenge in the treatment of melanoma. Current work was aimed to investigate; (a) Anticancer activity of a novel class of compound - Bromodomain and Extra-Terminal motif (BET) protein degrader in sensitive and vemurafenib-resistant melanoma (b) Preformulation studies and formulation development. ARV-825 (ARV), a molecule designed using PROteolysis-TArgeting Chimeric (PROTAC) technology, degrades BRD4 protein instead of merely inhibiting it. Based on extensive preformulation studies, ARV loaded self-nanoemulsifying preconcentrate (ARV-SNEP) was developed and optimized. ARV showed extremely poor aqueous solubility (<7 μg/mL) and pH dependent hydrolytic degradation. CaCO-2 cell uptake assay and human liver microsome studies proved that ARV is a substrate of CYP3A4 but not of P-gp efflux pump. Optimized ARV-SNEP spontaneously formed nanoglobules of 45.02 nm with zeta potential of -3.78 mV and significantly enhanced solubility of ARV in various aqueous and bio-relevant media. Most importantly, ARV showed promising cytotoxicity, anti-migration and apoptotic activity against vemurafenib-resistant melanoma cell...Continue Reading

Citations

May 15, 2020·Journal of Hematology & Oncology·Xin Li, Yongcheng Song
Aug 20, 2020·Seminars in Cancer Biology·Margarita E NeganovaGjumrakch Aliev
Apr 12, 2021·The Journal of Biological Chemistry·Shanique B Alabi, Craig M Crews

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