BRD4 PROTAC as a novel therapeutic approach for the treatment of vemurafenib resistant melanoma: Preformulation studies, formulation development and in vitro evaluation.
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2019
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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 cells. ARV-SNEP could be potentially novel therapeutic approach for the treatment of drug-resistant melanoma. This is the very first paper investigating a PROTAC class of molecule for the treatment of drug resistant cancer, preformulation and formulation studies.
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| Reference Key |
rathod2019brd4european
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| Authors | Rathod, Drishti;Fu, Yige;Patel, Ketan; |
| Journal | European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences |
| Year | 2019 |
| DOI |
S0928-0987(19)30303-3
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| URL | |
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