Ru(II) photocages enable precise control over enzyme activity with red light

Dmytro Havrylyuk, Austin C. Hachey, Alexander Fenton, David K. Heidary, Edith C. Glazer

Research output: Contribution to journalArticlepeer-review

4 Scopus citations

Abstract

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.

Original languageEnglish
Article number3636
JournalNature Communications
Volume13
Issue number1
DOIs
StatePublished - Dec 2022

Bibliographical note

Funding Information:
We gratefully acknowledge the support of the National Institute of General Medical Sciences of the National Institutes of Health under Award Numbers R01GM138882 and 5R01GM107586.

Publisher Copyright:
© 2022, The Author(s).

ASJC Scopus subject areas

  • Chemistry (all)
  • Biochemistry, Genetics and Molecular Biology (all)
  • General
  • Physics and Astronomy (all)

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