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

BRD4 PROTAC as a novel therapeutic approach for the treatment of vemurafenib resistant melanoma: Preformulation studies, formulation development and in vitro evaluation. Eur J Pharm Sci. 2019 Aug 05;:105039 Authors: Rathod D, Fu Y, Patel K 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 act...
Source: European Journal of Pharmaceutical Sciences - Category: Drugs & Pharmacology Authors: Tags: Eur J Pharm Sci Source Type: research