Development of a Retinal-Based Probe for the Profiling of Retinaldehyde Dehydrogenases in Cancer Cells | Zendy

Sebastiaan T. A. Koenders | Zendy; Lukas S. Wijaya | Zendy; Martje N. Erkelens | Zendy; Alexander T. Bakker | Zendy; Vera E. van der Noord | Zendy; Eva J. van Rooden | Zendy; Lindsey Burggraaff | Zendy; Pasquale C. Putter | Zendy; Else Botter | Zendy; Kim Wals | Zendy; Hans van den Elst | Zendy; Hans den Dulk | Zendy; Bogdan I. Florea | Zendy; Bob van de Water | Zendy; Gerard J. P. van Westen | Zendy; Reina E. Mebius | Zendy; Herman S. Overkleeft | Zendy; Sylvia E. Le Dévédec | Zendy; Mario van der Stelt | Zendy

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Development of a Retinal-Based Probe for the Profiling of Retinaldehyde Dehydrogenases in Cancer Cells

Author(s) -

Sebastiaan T. A. Koenders,

Lukas S. Wijaya,

Martje N. Erkelens,

Alexander T. Bakker,

Vera E. van der Noord,

Eva J. van Rooden,

Lindsey Burggraaff,

Pasquale C. Putter,

Else Botter,

Kim Wals,

Hans van den Elst,

Hans den Dulk,

Bogdan I. Florea,

Bob van de Water,

Gerard J. P. van Westen,

Reina E. Mebius,

Herman S. Overkleeft,

Sylvia E. Le Dévédec,

Mario van der Stelt

Publication year - 2019

Publication title -

acs central science

Language(s) - English

Resource type - Journals

SCImago Journal Rank - 4.893

H-Index - 76

eISSN - 2374-7951

pISSN - 2374-7943

DOI - 10.1021/acscentsci.9b01022

Subject(s) - retinaldehyde , aldehyde dehydrogenase , drug discovery , biochemistry , retinal , cancer cell , enzyme , biology , cytotoxicity , computational biology , chemistry , phenotypic screening , cancer , in vitro , genetics , gene , phenotype , rhodopsin

Retinaldehyde dehydrogenases belong to a superfamily of enzymes that regulate cell differentiation and are responsible for detoxification of anticancer drugs. Chemical tools and methods are of great utility to visualize and quantify aldehyde dehydrogenase (ALDH) activity in health and disease. Here, we present the discovery of a first-in-class chemical probe based on retinal, the endogenous substrate of retinal ALDHs. We unveil the utility of this probe in quantitating ALDH isozyme activity in a panel of cancer cells via both fluorescence and chemical proteomic approaches. We demonstrate that our probe is superior to the widely used ALDEFLUOR assay to explain the ability of breast cancer (stem) cells to produce all-trans retinoic acid. Furthermore, our probe revealed the cellular selectivity profile of an advanced ALDH1A1 inhibitor, thereby prompting us to investigate the nature of its cytotoxicity. Our results showcase the application of substrate-based probes in interrogating pathologically relevant enzyme activities. They also highlight the general power of chemical proteomics in driving the discovery of new biological insights and its utility to guide drug discovery efforts.

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