6F23

Complex between MTH1 and compound 16 (a 4-amino-7-azaindole derivative)

Summary for 6F23

• Entry DOI: 10.2210/pdb6f23/pdb
• Descriptor: 7,8-dihydro-8-oxoguanine triphosphatase, 4-[(2~{R})-2-phenylpyrrolidin-1-yl]-1~{H}-pyrrolo[2,3-b]pyridine, SULFATE ION, ... (5 entities in total)
• Functional Keywords: nudix, nucleotide hydrolase, inhibitor, oncology, hydrolase
• Biological source: Homo sapiens (Human)
• Cellular location: Isoform p18: Cytoplasm. Isoform p26: Cytoplasm: P36639
• Total number of polymer chains: 2
• Total formula weight: 38275.03

Authors

Viklund, J.,Tresaugues, L.,Talagas, A.,Andersson, M.,Ericsson, U.,Forsblom, R.,Ginman, T.,Hallberg, K.,Lindstrom, J.,Persson, L.,Silvander, C.,Rahm, F. (deposition date: 2017-11-23, release date: 2018-03-07, Last modification date: 2024-01-17)

Primary citation

Rahm, F.,Viklund, J.,Tresaugues, L.,Ellermann, M.,Giese, A.,Ericsson, U.,Forsblom, R.,Ginman, T.,Gunther, J.,Hallberg, K.,Lindstrom, J.,Persson, L.B.,Silvander, C.,Talagas, A.,Diaz-Saez, L.,Fedorov, O.,Huber, K.V.M.,Panagakou, I.,Siejka, P.,Gorjanacz, M.,Bauser, M.,Andersson, M.
Creation of a Novel Class of Potent and Selective MutT Homologue 1 (MTH1) Inhibitors Using Fragment-Based Screening and Structure-Based Drug Design.
J. Med. Chem., 61:2533-2551, 2018

PubMed Abstract: Recent literature has both suggested and questioned MTH1 as a novel cancer target. BAY-707 was just published as a target validation small molecule probe for assessing the effects of pharmacological inhibition of MTH1 on tumor cell survival, both in vitro and in vivo. (1) In this report, we describe the medicinal chemistry program creating BAY-707, where fragment-based methods were used to develop a series of highly potent and selective MTH1 inhibitors. Using structure-based drug design and rational medicinal chemistry approaches, the potency was increased over 10,000 times from the fragment starting point while maintaining high ligand efficiency and drug-like properties.

PubMed: 29485874
DOI: 10.1021/acs.jmedchem.7b01884

Experimental method

X-RAY DIFFRACTION (1.84 Å)