计算机模拟发现 5'-修饰的 7-脱氧-7-乙炔基-4'-硫腺苷作为 HASPIN 抑制剂及其与 PLK1 抑制剂的协同抗癌作用,ACS Central Science

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计算机模拟发现 5'-修饰的 7-脱氧-7-乙炔基-4'-硫腺苷作为 HASPIN 抑制剂及其与 PLK1 抑制剂的协同抗癌作用
ACS Central Science ( IF 12.7 ) Pub Date : 2023-05-11 , DOI: 10.1021/acscentsci.3c00332
Eun-Ji Kwon ₁ , Karishma K Mashelkar ₁ , Juhee Seo ₁ , Yoon-Ze Shin ₁ , Kisu Sung ₁ , Sung Chul Jang _{1,

2} , Sang Won Cheon ₁ , Haeseung Lee _{3,

4} , Hyuk Woo Lee ₅ , Gyudong Kim ₆ , Byung Woo Han _{1,

7} , Sang Kook Lee _{1,

2} , Lak Shin Jeong _{1,

5,

7} , Hyuk-Jin Cha _{1,

7}

Affiliation

尽管遗传扰动导致大多数有丝分裂激酶在胚胎中死亡，但组蛋白 H3 有丝分裂激酶 HASPIN 的缺失在小鼠模型中没有显示出不良影响，这使 HASPIN 成为抗癌治疗的一个有前景的靶点。然而，从传统药效团开发 HASPIN 抑制剂提出了技术挑战，因为这种非典型激酶与真核蛋白激酶略有相似之处。通过高基因毒性对细胞毒性 4'-硫腺苷类似物进行化学修饰，产生了几种新型非基因毒性激酶抑制剂。利用与已知化合物和 KINOMEscan 图谱的转录组和化学相似性的计算机方法揭示了 HASPIN 抑制剂 LJ4827。LJ4827 作为 HASPIN 抑制剂的特异性和效力通过体外激酶测定和 X 射线晶体学得到验证。LJ4827 抑制 HASPIN 会降低组蛋白 H3 磷酸化，并阻碍 Aurora B 在癌细胞着丝粒中的募集，但在非癌细胞中则不然。通过对肺癌患者的转录组分析，PLK1 被确定为可药物协同伴侣，以补充 HASPIN 抑制。LJ4827 对 PLK1 的化学或遗传干扰可在体外和体内产生明显的肺癌细胞毒性。因此，LJ4827是一种新型抗癌药物，通过有效抑制HASPIN选择性阻碍癌症有丝分裂，同时干扰HASPIN和PLK1是一种有前景的肺癌治疗策略。PLK1 被确定为可药物协同伴侣，以补充 HASPIN 抑制。LJ4827 对 PLK1 的化学或遗传干扰可在体外和体内产生明显的肺癌细胞毒性。因此，LJ4827是一种新型抗癌药物，通过有效抑制HASPIN选择性阻碍癌症有丝分裂，同时干扰HASPIN和PLK1是一种有前景的肺癌治疗策略。PLK1 被确定为可药物协同伴侣，以补充 HASPIN 抑制。LJ4827 对 PLK1 的化学或遗传干扰可在体外和体内产生明显的肺癌细胞毒性。因此，LJ4827是一种新型抗癌药物，通过有效抑制HASPIN选择性阻碍癌症有丝分裂，同时干扰HASPIN和PLK1是一种有前景的肺癌治疗策略。

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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 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.

更新日期：2023-05-11

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