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.
DMU2139是一种有效的CYP1B1抑制剂，IC50值为9nM[1]。由于疏水性萘基的存在，DMU2139可与血红素配位，并通过π-π堆积与疏水性残基Phe134和Phe231相互作用[2]。DMU2139已与顺铂联合使用，以克服CYP1B1介导的耐药性，使癌细胞重新对顺铂敏感[3]。
在体内，通过腹腔注射，每4天给药一次，持续24天，联合使用DMU2139（30mg/kg）和奥拉帕利（50mg/kg），在A2780细胞的异种移植小鼠模型中显著抑制了肿瘤生长[4]。