Identification and characterization of novel ligase I inhibitors

Pandey, Monica and Kumar, Sujeet and Goldsmith, Gunaseelan and Srivastava, Mrinal and Elango, Santhini and Shameem, Mohammad and Bannerjee, Dibyendu and Choudhary, Bibha and Karki, Subhas S and Raghavan, Sathees C (2017) Identification and characterization of novel ligase I inhibitors. In: MOLECULAR CARCINOGENESIS, 56 (2). pp. 550-566.

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Abstract

The terminal step of ligation of single and/or double-strand breaks during physiological processes such as DNA replication, repair and recombination requires participation of DNA ligases in all mammals. DNA Ligase I has been well characterised to play vital roles during these processes. Considering the indispensable role of DNA Ligase I, a therapeutic strategy to impede proliferation of cancer cells is by using specific small molecule inhibitors against it. In the present study, we have designed and chemically synthesised putative DNA Ligase I inhibitors. Based on various biochemical and biophysical screening approaches, we identify two prospective DNA Ligase I inhibitors, SCR17 and SCR21. Both the inhibitors blocked ligation of nicks on DNA in a concentration-dependent manner, when catalysed by cell-free extracts or purified Ligase I. Docking studies in conjunction with biolayer interferometry and gel shift assays revealed that both SCR17 and SCR21 can bind to Ligase I, particularly to the DNA Binding Domain of Ligase I with KD values in nanomolar range. The inhibitors did not show significant affinity towards DNA Ligase III and DNA Ligase IV. Further, addition of Ligase I could restore the joining, when the inhibitors were treated with testicular cell-free extracts. Ex vivo studies using multiple assays showed that even though cell death was limited in the presence of inhibitors in cancer cells, their proliferation was compromised. Hence, we identify two promising DNA Ligase I inhibitors, which can be used in biochemical and cellular assays, and could be further modified and optimised to target cancer cells. (c) 2016 Wiley Periodicals, Inc.

Item Type:	Journal Article
Publication:	MOLECULAR CARCINOGENESIS
Publisher:	WILEY-BLACKWELL, 111 RIVER ST, HOBOKEN 07030-5774, NJ USA
Additional Information:	Copy right for this article belongs to the WILEY-BLACKWELL, 111 RIVER ST, HOBOKEN 07030-5774, NJ USA
Department/Centre:	Division of Biological Sciences > Biochemistry
Date Deposited:	09 Mar 2017 04:46
Last Modified:	09 Mar 2017 04:46
URI:	http://eprints.iisc.ac.in/id/eprint/56327

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