6T5J

Structure of NUDT15 in complex with inhibitor TH1760

Summary for 6T5J

• Entry DOI: 10.2210/pdb6t5j/pdb
• Descriptor: Probable 8-oxo-dGTP diphosphatase NUDT15, 6-[4-(1~{H}-indol-5-ylcarbonyl)piperazin-1-yl]sulfonyl-3~{H}-1,3-benzoxazol-2-one, MAGNESIUM ION, ... (5 entities in total)
• Functional Keywords: nudix hydrolase, inhibitor, hydrolase
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 2
• Total formula weight: 38291.02

Authors

Carter, M.,Rehling, D.,Desroses, M.,Zhang, S.M.,Hagenkort, A.,Valerie, N.C.K.,Helleday, T.,Stenmark, P. (deposition date: 2019-10-16, release date: 2020-07-29, Last modification date: 2024-01-24)

Primary citation

Zhang, S.M.,Desroses, M.,Hagenkort, A.,Valerie, N.C.K.,Rehling, D.,Carter, M.,Wallner, O.,Koolmeister, T.,Throup, A.,Jemth, A.S.,Almlof, I.,Loseva, O.,Lundback, T.,Axelsson, H.,Regmi, S.,Sarno, A.,Kramer, A.,Pudelko, L.,Brautigam, L.,Rasti, A.,Gottmann, M.,Wiita, E.,Kutzner, J.,Schaller, T.,Kalderen, C.,Cazares-Korner, A.,Page, B.D.G.,Krimpenfort, R.,Eshtad, S.,Altun, M.,Rudd, S.G.,Knapp, S.,Scobie, M.,Homan, E.J.,Berglund, U.W.,Stenmark, P.,Helleday, T.
Development of a chemical probe against NUDT15.
Nat.Chem.Biol., 16:1120-1128, 2020

PubMed Abstract: The NUDIX hydrolase NUDT15 was originally implicated in sanitizing oxidized nucleotides, but was later shown to hydrolyze the active thiopurine metabolites, 6-thio-(d)GTP, thereby dictating the clinical response of this standard-of-care treatment for leukemia and inflammatory diseases. Nonetheless, its physiological roles remain elusive. Here, we sought to develop small-molecule NUDT15 inhibitors to elucidate its biological functions and potentially to improve NUDT15-dependent chemotherapeutics. Lead compound TH1760 demonstrated low-nanomolar biochemical potency through direct and specific binding into the NUDT15 catalytic pocket and engaged cellular NUDT15 in the low-micromolar range. We also employed thiopurine potentiation as a proxy functional readout and demonstrated that TH1760 sensitized cells to 6-thioguanine through enhanced accumulation of 6-thio-(d)GTP in nucleic acids. A biochemically validated, inactive structural analog, TH7285, confirmed that increased thiopurine toxicity takes place via direct NUDT15 inhibition. In conclusion, TH1760 represents the first chemical probe for interrogating NUDT15 biology and potential therapeutic avenues.

PubMed: 32690945
DOI: 10.1038/s41589-020-0592-z

Experimental method

X-RAY DIFFRACTION (1.6 Å)