Identification of multidentate tyrosyl-DNA phosphodiesterase 1 (TDP1) inhibitors that simultaneously access the DNA, protein and catalytic-binding sites by oxime diversification.

Autor:	Zhao XZ; Chemical Biology Laboratory, Center for Cancer Research, National Cancer Institute, National Institutes of Health Frederick MD USA xuezhi.zhao@nih.gov., Wang W; Developmental Therapeutics Branch & Laboratory of Molecular Pharmacology, Center for Cancer Research, National Cancer Institute, National Institutes of Health Bethesda MD USA., Lountos GT; Basic Science Program, Frederick National Laboratory for Cancer Research Frederick MD USA., Kiselev E; Developmental Therapeutics Branch & Laboratory of Molecular Pharmacology, Center for Cancer Research, National Cancer Institute, National Institutes of Health Bethesda MD USA., Tropea JE; Center for Structural Biology, Center for Cancer Research, National Cancer Institute Frederick MD USA., Needle D; Center for Structural Biology, Center for Cancer Research, National Cancer Institute Frederick MD USA., Pommier Y; Developmental Therapeutics Branch & Laboratory of Molecular Pharmacology, Center for Cancer Research, National Cancer Institute, National Institutes of Health Bethesda MD USA., Burke TR Jr; Chemical Biology Laboratory, Center for Cancer Research, National Cancer Institute, National Institutes of Health Frederick MD USA xuezhi.zhao@nih.gov.
Jazyk:	angličtina
Zdroj:	RSC chemical biology [RSC Chem Biol] 2023 Mar 27; Vol. 4 (5), pp. 334-343. Date of Electronic Publication: 2023 Mar 27 (Print Publication: 2023).
DOI:	10.1039/d2cb00230b
Abstrakt:	Tyrosyl-DNA phosphodiesterase 1 (TDP1) is a member of the phospholipase D family that can downregulate the anticancer effects of the type I topoisomerase (TOP1) inhibitors by hydrolyzing the 3'-phosphodiester bond between DNA and the TOP1 residue Y723 in the critical stalled intermediate that is the foundation of TOP1 inhibitor mechanism of action. Thus, TDP1 antagonists are attractive as potential enhancers of TOP1 inhibitors. However, the open and extended nature of the TOP1-DNA substrate-binding region has made the development of TDP1 inhibitors extremely challenging. In this study, starting from our recently identified small molecule microarray (SMM)-derived TDP1-inhibitory imidazopyridine motif, we employed a click-based oxime protocol to extend the parent platform into the DNA and TOP1 peptide substrate-binding channels. We applied one-pot Groebke-Blackburn-Bienayme multicomponent reactions (GBBRs) to prepare the needed aminooxy-containing substrates. By reacting these precursors with approximately 250 aldehydes in microtiter format, we screened a library of nearly 500 oximes for their TDP1 inhibitory potencies using an in vitro florescence-based catalytic assay. Select hits were structurally explored as their triazole- and ether-based isosteres. We obtained crystal structures of two of the resulting inhibitors bound to the TDP1 catalytic domain. The structures reveal that the inhibitors form hydrogen bonds with the catalytic His-Lys-Asn triads ("HKN" motifs: H263, K265, N283 and H493, K495, N516), while simultaneously extending into both the substrate DNA and TOP1 peptide-binding grooves. This work provides a structural model for developing multivalent TDP1 inhibitors capable of binding in a tridentate fashion with a central component situated within the catalytic pocket and extensions that project into both the DNA and TOP1 peptide substrate-binding regions. Competing Interests: Aspects of the work presented are contained within one or more patent applications. The authors declare that there is no conflict of interest. (This journal is © The Royal Society of Chemistry.)
Databáze:	MEDLINE
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