Department of Chemistry, University of Kentucky, Lexington, KY, 40506, USA.
Nat Commun. 2022 Jun 25;13(1):3636. doi: 10.1038/s41467-022-31269-5.
The cytochrome P450 family of enzymes (CYPs) are important targets for medicinal chemistry. Recently, CYP1B1 has emerged as a key player in chemotherapy resistance in the treatment of cancer. This enzyme is overexpressed in a variety of tumors, and is correlated with poor treatment outcomes; thus, it is desirable to develop CYP1B1 inhibitors to restore chemotherapy efficacy. However, possible off-target effects, such as inhibition of liver CYPs responsible for first pass metabolism, make selective inhibition a high priority to avoid possible drug-drug interactions and toxicity. Here we describe the creation of light-triggered CYP1B1 inhibitors as "prodrugs", and achieve >6000-fold improvement in potency upon activation with low energy (660 nm) light. These systems provide a selectivity index of 4,000-100,000 over other off-target CYPs. One key to the design was the development of coordinating CYP1B1 inhibitors, which suppress enzyme activity at pM concentrations in live cells. The metal binding group enforces inhibitor orientation in the active site by anchoring to the iron. The second essential component was the biologically compatible Ru(II) scaffold that cages the inhibitors before photochemical release. These Ru(II) photocages are anticipated to provide similar selectivity and control for any coordinating CYP inhibitors.
细胞色素 P450 酶家族（CYPs）是药物化学的重要靶点。最近，CYP1B1 已成为癌症化疗耐药治疗中的关键因素。这种酶在多种肿瘤中过度表达，与治疗效果不佳相关；因此，开发 CYP1B1 抑制剂以恢复化疗疗效是很有必要的。然而，可能的脱靶效应，如抑制负责首过代谢的肝脏 CYP，使得选择性抑制成为避免可能的药物相互作用和毒性的首要任务。在这里，我们描述了光触发 CYP1B1 抑制剂作为“前药”的创建，并在使用低能量（660nm）光激活时获得了超过 6000 倍的效力提高。这些系统在其他脱靶 CYP 上提供了 4000-100000 的选择性指数。设计的一个关键是开发配位 CYP1B1 抑制剂，这些抑制剂在活细胞中以皮摩尔浓度抑制酶活性。金属结合基团通过与铁结合来强制抑制剂在活性部位的取向。第二个必不可少的组成部分是生物相容的 Ru（II）支架，它在光化学释放前将抑制剂固定在其中。预计这些 Ru（II）光笼将为任何配位 CYP 抑制剂提供类似的选择性和控制。
