DMU2139 is a potent CYP1B1 inhibitor, with an IC50 value of 9nM[1]. DMU2139 coordinates with heme and interacts with the hydrophobic residues Phe134 and Phe231 through p-p stacking since the hydrophobic naphthyl group[2]. DMU2139 has been used in combination with cisplatin to overcome the resistance mediated by CYP1B1 and make cancer cells re-sensitized to cisplatin[3].
In vivo, the combination treatment of DMU2139 (30mg/kg) and olaparib (50mg/kg), administered by intraperitoneal injection every 4 days for 24 days, significantly inhibited tumor growth in a xenograft mouse model of A2780 cells[4].
References:
[1] Horley N J, Beresford K J M, Chawla T, et al. Discovery and characterization of novel CYP1B1 inhibitors based on heterocyclic chalcones: Overcoming cisplatin resistance in CYP1B1-overexpressing lines[J]. European journal of medicinal chemistry, 2017, 129: 159-174.
[2] Raju B, Choudhary S, Narendra G, et al. Molecular modeling approaches to address drug-metabolizing enzymes (DMEs) mediated chemoresistance: a review[J]. Drug Metabolism Reviews, 2021, 53(1): 45-75.
[3] Alsubait A, Aldossary W, Rashid M, et al. CYP1B1 gene: Implications in glaucoma and cancer[J]. Journal of cancer, 2020, 11(16): 4652.
[4] Xue Y, Yin T, Yuan S, et al. CYP1B1 promotes PARPi-resistance via histone H1. 4 interaction and increased chromatin accessibility in ovarian cancer[J]. Drug Resistance Updates, 2024, 77: 101151.