In Silico Discovery of 5′-Modified 7‑Deoxy-7-ethynyl-4′-thioadenosine as a HASPIN Inhibitor and Its Synergistic Anticancer Effect with the PLK1 Inhibitor

Despite genetic perturbations resulting in embryo lethality for most mitotic kinases, loss of the histone H3 mitotic kinase HASPIN reveals no adverse effect in mice models, establishing HASPIN as a promising target for anticancer therapy. However, developing a HASPIN inhibitor from conventional phar...

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Published in:	ACS central science Vol. 9; no. 6; pp. 1140 - 1149
Main Authors:	Kwon, Eun-Ji, Mashelkar, Karishma K., Seo, Juhee, Shin, Yoon-Ze, Sung, Kisu, Jang, Sung Chul, Cheon, Sang Won, Lee, Haeseung, Lee, Hyuk Woo, Kim, Gyudong, Han, Byung Woo, Lee, Sang Kook, Jeong, Lak Shin, Cha, Hyuk-Jin
Format:	Journal Article
Language:	English
Published:	United States American Chemical Society 28-06-2023
Subjects:	Animal models Anticancer properties Aurora B protein Biocompatibility Cancer Cell cycle Centromeres Chemical fingerprinting Crystallography Cytotoxicity Genotoxicity Histone H3 Histones Hydrogen bonds Kinases Lethality Lung cancer Mitosis Perturbation Pharmacophores Phosphorylation Polo-like kinase 1 Similarity Stem cells Transcriptomes Transcriptomics X-ray crystallography Yeast
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Summary:	Despite genetic perturbations resulting in embryo lethality for most mitotic kinases, loss of the histone H3 mitotic kinase HASPIN reveals no adverse effect in mice models, establishing HASPIN as a promising target for anticancer therapy. However, developing a HASPIN inhibitor from conventional pharmacophores poses a technical challenge as this atypical kinase shares slight similarities with eukaryotic protein kinases. Chemically modifying a cytotoxic 4′-thioadenosine analogue through high genotoxicity yielded several novel nongenotoxic kinase inhibitors. In silico apporoaches utilizing transcriptomic and chemical similarities with known compounds and KINOMEscan profiles unveiled the HASPIN inhibitor LJ4827. LJ4827’s specificity and potency as a HASPIN inhibitor were verified through in vitro kinase assay and X-ray crystallography. HASPIN inhibition by LJ4827 reduced histone H3 phosphorylation and impeded Aurora B recruitment in cancer cell centromeres but not in noncancer cells. Through transcriptome analysis of lung cancer patients, PLK1 was determined as a druggable synergistic partner to complement HASPIN inhibition. Chemical or genetic PLK1 perturbation with LJ4827 effectuated pronounced lung cancer cytotoxicity in vitro and in vivo. Therefore, LJ4827 is a novel anticancer therapeutic for selectively impeding cancer mitosis through potent HASPIN inhibition, and simultaneous HASPIN and PLK1 interference is a promising therapeutic strategy for lung cancer.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 This paper was published on May 11, 2023. The name of a substance was corrected in the title, and the new version was reposted on May 22, 2023.
ISSN:	2374-7943 2374-7951
DOI:	10.1021/acscentsci.3c00332