Eun-Ji Kwon,1‡ Karishma K. Mashelkar,1‡ Juhee Seo1, Yoon-Ze Shin1, Kisu Sung1, Sung Chul Jang2, Sang Won Cheon1, Haeseung Lee3, Hyuk Woo Lee4, Gyudong Kim5, Byung Woo Han6, Sang Kook Lee2, Lak Shin Jeong,4,6* and Hyuk-Jin Cha6*
1College of Pharmacy, Seoul National University, Seoul 08826, Republic of Korea
2College of Pharmacy and Natural Products Research Institute, Seoul National University, Seoul 08826, Republic of Korea
3College of Pharmacy and Research Institute for Drug Development, Pusan National University, Busan 46241, Republic of Korea
4Future Medicine Company, Limited, Seongnam, Gyeonggi-do 13449, Republic of Korea
5College of Pharmacy, and Research Institute of Drug Development, Chonnam National University, Gwangju 61469, Republic of Korea
6College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul 08826, Republic of Korea
E.-J.K. and K.K.M.: These authors contributed equally.
Corresponding Authors : Lak Shin Jeong, Hyuk-Jin Cha
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.