Structure of the month - January 2018
Targeted NUDT5 inhibitors block hormone signaling in breast cancer cells
Brent D.G. Page1, Nicholas C.K. Valerie1, Roni H.G. Wright2,3, Olov Wallner1, Rebecka Isaksson1, Megan Carter4, Sean G. Rudd1, Olga Loseva1, Ann-Sofie Jemth1, Ingrid Almlöf1, Jofre Font-Mateu2,3, Sabin Llona-Minguez1, Pawel Baranczewski5, Fredrik Jeppsson1, Evert Homan1, Helena Almqvist6, Hanna Axelsson6, Shruti Regmi6, Anna-Lena Gustavsson6, Thomas Lundbäck6, Martin Scobie1, Kia Strömberg1, Pål Stenmark4, Miguel Beato2,3 & Thomas Helleday1
With a diverse network of substrates, NUDIX hydrolases have emerged as a key family of nucleotide-metabolizing enzymes. NUDT5 (also called NUDIX5) has been implicated in ADP- ribose and 8-oxo-guanine metabolism and was recently identified as a rheostat of hormone- dependent gene regulation and proliferation in breast cancer cells. Here, we further elucidate the physiological relevance of known NUDT5 substrates and underscore the biological requirement for NUDT5 in gene regulation and proliferation of breast cancer cells. We confirm the involvement of NUDT5 in ADP-ribose metabolism and dissociate a relationship to oxidized nucleotide sanitation. Furthermore, we identify potent NUDT5 inhibitors, which are optimized to promote maximal NUDT5 cellular target engagement by CETSA. Lead compound, TH5427, blocks progestin-dependent, PAR-derived nuclear ATP synthesis and subsequent chromatin remodeling, gene regulation and proliferation in breast cancer cells. We herein present TH5427 as a promising, targeted inhibitor that can be used to further study NUDT5 activity and ADP-ribose metabolism.
1Science for Life Laboratory, Division of Translational Medicine and Chemical Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Solna SE-171 21, Sweden.
2Centre de Regulació Genòmica (CRG), Barcelona Institute for Science and Technology, Barcelona E-09003, Spain.
3Universitat Pompeu Fabra, Barcelona E-08003, Spain.
4Department of Biochemistry and Biophysics, Stockholm University, Stockholm SE-106 91, Sweden.
5Uppsala University Drug Optimization and Pharmaceutical Profiling Platform, Department of Pharmacy, Uppsala University, Uppsala SE-751 23, Sweden.
6Chemical Biology Consortium Sweden, Science for Life Laboratory, Division of Translational Medicine and Chemical Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Solna SE-171 21, Sweden.
Corresponding authors:Brent D.G. Page <email@example.com>, Thomas Helleday <firstname.lastname@example.org>