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

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

doi:10.1021/acscentsci.9b01022

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

ACS Cent Sci. 2019 Dec 26;5(12):1965-1974. doi: 10.1021/acscentsci.9b01022. Epub 2019 Dec 12.

Authors

Sebastiaan T A Koenders^{1

2}, Lukas S Wijaya³, Martje N Erkelens⁴, Alexander T Bakker¹, Vera E van der Noord³, Eva J van Rooden¹, Lindsey Burggraaff⁵, Pasquale C Putter¹, Else Botter¹, Kim Wals^{1

2}, Hans van den Elst⁶, Hans den Dulk¹, Bogdan I Florea⁶, Bob van de Water³, Gerard J P van Westen⁵, Reina E Mebius⁴, Herman S Overkleeft⁶, Sylvia E Le Dévédec³, Mario van der Stelt^{1

2}

Affiliations

¹ Department of Molecular Physiology, Leiden Institute of Chemistry, Leiden University, Leiden 2300 RA, The Netherlands.
² Oncode Institute, Utrecht 3521 AL, The Netherlands.
³ Cancer Therapeutics and Drug Safety, Division of Drug Discovery and Safety, Leiden Academic Centre for Drug Research, Leiden University, Leiden 2300 RA, The Netherlands.
⁴ Department of Molecular Cell Biology and Immunology, Amsterdam University Medical Centra, Amsterdam 1081 HV, The Netherlands.
⁵ Computational Drug Discovery, Division of Drug Discovery and Safety, Leiden Academic Centre for Drug Research, Leiden University, Leiden 2300 RA, The Netherlands.
⁶ Department of Bio-Organic Synthesis, Leiden Institute of Chemistry, Leiden University, Leiden 2300 RA, The Netherlands.

Abstract

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.