8RIY

Human NUDT5 with ibrutinib derivative

This is a non-PDB format compatible entry.

Summary for 8RIY

• Entry DOI: 10.2210/pdb8riy/pdb
• Descriptor: ADP-sugar pyrophosphatase, 1-(1-methylpiperidin-4-yl)-3-(4-phenoxyphenyl)pyrazolo[3,4-d]pyrimidin-4-amine (3 entities in total)
• Functional Keywords: nudt5, nudix, hydrolase
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 2
• Total formula weight: 47073.11

Authors

Balikci-Akil, E.,Elkins, J.M.,Huber, K.V.M. (deposition date: 2023-12-19, release date: 2024-05-01, Last modification date: 2024-05-22)

Primary citation

Balikci, E.,Marques, A.M.C.,Bauer, L.G.,Seupel, R.,Bennett, J.,Raux, B.,Buchan, K.,Simelis, K.,Singh, U.,Rogers, C.,Ward, J.,Cheng, C.,Szommer, T.,Schutzenhofer, K.,Elkins, J.M.,Sloman, D.L.,Ahel, I.,Fedorov, O.,Brennan, P.E.,Huber, K.V.M.
Unexpected Noncovalent Off-Target Activity of Clinical BTK Inhibitors Leads to Discovery of a Dual NUDT5/14 Antagonist.
J.Med.Chem., 67:7245-7259, 2024

PubMed Abstract: Cofactor mimicry represents an attractive strategy for the development of enzyme inhibitors but can lead to off-target effects due to the evolutionary conservation of binding sites across the proteome. Here, we uncover the ADP-ribose (ADPr) hydrolase NUDT5 as an unexpected, noncovalent, off-target of clinical BTK inhibitors. Using a combination of biochemical, biophysical, and intact cell NanoBRET assays as well as X-ray crystallography, we confirm catalytic inhibition and cellular target engagement of NUDT5 and reveal an unusual binding mode that is independent of the reactive acrylamide warhead. Further investigation of the prototypical BTK inhibitor ibrutinib also revealed potent inhibition of the largely unstudied NUDIX hydrolase family member NUDT14. By exploring structure-activity relationships (SARs) around the core scaffold, we identify a potent, noncovalent, and cell-active dual NUDT5/14 inhibitor. Cocrystallization experiments yielded new insights into the NUDT14 hydrolase active site architecture and inhibitor binding, thus providing a basis for future chemical probe design.

PubMed: 38635563
DOI: 10.1021/acs.jmedchem.4c00072

Experimental method

X-RAY DIFFRACTION (2.288 Å)