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 (CYP) 是药物化学的重要靶标。最近，CYP1B1 已成为癌症治疗中化疗耐药的关键参与者。这种酶在多种肿瘤中过度表达，并与不良治疗结果相关；因此，需要开发 CYP1B1 抑制剂来恢复化疗疗效。然而，可能的脱靶效应，例如抑制负责首过代谢的肝脏 CYP，使选择性抑制成为避免可能的药物相互作用和毒性的重中之重。在这里，我们将光触发 CYP1B1 抑制剂的产生描述为“前药”，并在用低能 (660 nm) 光激活时实现超过 6000 倍的效力提高。与其他脱靶 CYP 相比，这些系统提供 4,000–100,000 的选择性指数。设计的一个关键是开发协调的 CYP1B1 抑制剂，它可以抑制活细胞中 pM 浓度下的酶活性。金属结合基团通过锚定到铁上来加强活性位点的抑制剂取向。第二个重要组成部分是生物相容的 Ru(II) 支架，它在光化学释放之前将抑制剂笼罩住。预计这些 Ru(II) 光笼可为任何协调的 CYP 抑制剂提供类似的选择性和控制。第二个重要组成部分是生物相容的 Ru(II) 支架，它在光化学释放之前将抑制剂笼罩住。预计这些 Ru(II) 光笼可为任何协调的 CYP 抑制剂提供类似的选择性和控制。第二个重要组成部分是生物相容的 Ru(II) 支架，它在光化学释放之前将抑制剂笼罩住。预计这些 Ru(II) 光笼可为任何协调的 CYP 抑制剂提供类似的选择性和控制。