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bioRxiv · 10.1101/2022.09.01.506282

Identification of a novel HASPIN inhibitor and its synergism with the PLK1 inhibitor

Kwon, E.-J.·Mashelkar, K.·Seo, J.·Shin, Y.·Sung, K.·Jang, S. C.·Cheon, S. W.·Lee, H.·Han, B. W.·Jeong, L. S.·Cha, H.-J.
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Abstract

BackgroundHASPIN, a mitotic kinase for Histone H3, is a promising target for anti-cancer therapy. However, as HASPIN is an atypical kinase with low similarity to eukaryotic protein kinases, development of a HASPIN inhibitor from the conventional pharmacophore of kinase inhibitors would be technically challenging. MethodsChemical modifications of a cytotoxic 4-thioadenosine analogue with high genotoxicity and multiple kinomescan profiles were performed to produce a novel non-genotoxic kinase inhibitor, LJ4827. The mode of action of this inhibitor with clear anti-cancer activity was inferred based on transcriptomic and chemical similarity to known drugs. ResultsThe specificity and potency of LJ4827 as a HASPIN inhibitor were validated by in vitro kinase screening and subsequent X-ray crystallography. As predicted, LJ4827 treatment delayed mitosis by clear inhibition of the recruitment of Aurora B at the centromere in cancer cells, without a genotoxic response. Through transcriptome analysis of lung cancer patients, PLK1 was predicted as a druggable synergistic partner to complement HASPIN inhibition. Cotreatment with the PLK1 inhibitor BI2536 and LJ4827 led to pronounced cytotoxicity of lung cancers in vitro and in vivo. ConclusionSimultaneous inhibition of both HASPIN and PLK1 is a promising therapeutic strategy for lung cancers.

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Kwon, E.-J., Mashelkar, K., Seo, J., Shin, Y., Sung, K., Jang, S. C., Cheon, S. W., Lee, H., Han, B. W., Jeong, L. S., Cha, H.-J.. 2022-09-03. Identification of a novel HASPIN inhibitor and its synergism with the PLK1 inhibitor. https://doi.org/10.1101/2022.09.01.506282

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