Polo-box PLK1 Inhibitors Target Tumors Resistant to ATP Competitive Compounds

Polo-like kinase1(PLK1)是调节细胞进入和进展的中心分子 有丝分裂。许多研究证实PLK1是一个抗肿瘤的药物靶点，它的抑制作用是 对癌细胞有很强的抗增殖作用。然而，最近的数据表明，有两个 传统方法阻断PLK1的激酶活性的主要缺点。第一, 一般的Kinome和PLK家族特异性都是ATP竞争性化合物的一个问题，因为 它们通常抑制Polo-Kinase家族中的所有类似物(包括已知的肿瘤PLK3 抑制者)。其次，最近的一项研究表明，活性部位的单点突变 PLK1(Cys67Val)导致对结构上不同的ATP竞争性的完全抵抗 目前正在进行临床试验的抑制剂，表明临床上出现了耐药性 对这些特工的指控几乎是板上钉钉。因此，一个不同于以 催化域是迫切需要的。PPI制药公司将开发PLK1选择性非 三磷酸腺苷竞争性抑制剂作为有效的抗肿瘤治疗药物 对传统的激酶抑制剂耐药的活性位点突变体。这类化合物将具有 作为抗肿瘤药物开发的巨大潜力，降低了肿瘤的可能性 抵抗和偏离目标的效果。

Polo-like kinase 1 (PLK1) is a central player in regulating entry into and progression through mitosis. Many studies have validated PLK1 as an anti-tumor drug target, and its inhibition is potently anti-proliferative to cancer cells. However, recent data suggests that there are two major disadvantages of the conventional approach to blocking the kinase activity of PLK1. First, both general kinome and PLK family specificity is an issue with ATP competitive compounds as they commonly inhibit all paralogs in the Polo-kinase family (including PLK3, a known tumor suppressor). Second, a recent study indicates that a single point mutant in the active site of PLK1 (Cys67Val) results in complete resistance to structurally distinct ATP competitive inhibitors currently in clinical trials, suggesting that the emergence of resistance in the clinic against these agents is a near certainty. Therefore a strategy different from targeting the catalytic domains is urgently needed. PPI Pharmaceuticals will develop PLK1 selective non- ATP competitive inhibitors as effective anti-tumor therapeutics that retain activity against active site mutants resistant to conventional kinase inhibitors. Such compounds will have significant potential for development as anti-tumor agents with decreased likelihood of tumor resistance and off-target effects.