Identification of a ligand binding hot spot and structural motifs replicating aspects of tyrosyl-DNA phosphodiesterase I (TDP1) phosphoryl recognition by crystallographic fragment cocktail screening

Journal Article · Fri Jun 14 00:00:00 EDT 2019 · Nucleic Acids Research

DOI:https://doi.org/10.1093/nar/gkz515· OSTI ID:1575036

Lountos, George T. ^[1]; Zhao, Xue Zhi ^[2]; Kiselev, Evgeny ^[3]; Tropea, Joseph E. ^[4]; Needle, Danielle ^[4]; Pommier, Yves ^[3]; Burke, Terrence R. ^[2]; Waugh, David S.  ^[4]

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1. Basic Science Program, Frederick National Laboratory for Cancer Research, Frederick, MD 21702, USA
2. Chemical Biology Laboratory, Center for Cancer Research, National Cancer Institute, Frederick, MD 21702, USA
3. Developmental Therapeutics Branch & Laboratory of Molecular Pharmacology, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA
4. Macromolecular Crystallography Laboratory, Center for Cancer Research, National Cancer Institute, Frederick, MD 21702, USA

Tyrosyl DNA-phosphodiesterase I (TDP1) repairs type IB topoisomerase (TOP1) cleavage complexes generated by TOP1 inhibitors commonly used as anticancer agents. TDP1 also removes DNA 3' end blocking lesions generated by chain-terminating nucleosides and alkylating agents, and base oxidation both in the nuclear and mitochondrial genomes. Combination therapy with TDP1 inhibitors is proposed to synergize with topoisomerase targeting drugs to enhance selectivity against cancer cells exhibiting deficiencies in parallel DNA repair pathways. A crystallographic fragment screening campaign against the catalytic domain of TDP1 was conducted to identify new lead compounds. Crystal structures revealed two fragments that bind to the TDP1 active site and exhibit inhibitory activity against TDP1. These fragments occupy a similar position in the TDP1 active site as seen in prior crystal structures of TDP1 with bound vanadate, a transition state mimic. Using structural insights into fragment binding, several fragment derivatives have been prepared and evaluated in biochemical assays. These results demonstrate that fragment-based methods can be a highly feasible approach toward the discovery of small-molecule chemical scaffolds to target TDP1, and for the first time, we provide co-crystal structures of small molecule inhibitors bound to TDP1, which could serve for the rational development of medicinal TDP1 inhibitors.

• Research Organization: Argonne National Laboratory (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
• Sponsoring Organization: NCINIH
• OSTI ID: 1575036
• Journal Information: Nucleic Acids Research, Vol. 47, Issue 19; ISSN 0305-1048
• Publisher: Oxford University Press
• Country of Publication: United States
• Language: ENGLISH