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

Polo样激酶1（PLK1）是调节进入和进展的核心参与者， 分裂。许多研究已经证实PLK1是一个抗肿瘤药物靶点，其抑制作用是通过抑制PLK1的表达来实现的。 对癌细胞有很强的抗增殖作用。然而，最近的数据显示， 这是阻断PLK1激酶活性的常规方法的主要缺点。第一、 一般激酶组和PLK家族特异性都是ATP竞争性化合物的问题， 它们通常抑制Polo激酶家族中的所有旁系同源物（包括PLK3，一种已知的肿瘤 抑制子）。其次，最近的一项研究表明，在活性位点的单点突变， PLK1（Cys67Val）导致对结构上不同的ATP竞争性 抑制剂目前在临床试验中，这表明在临床上出现耐药性， 对这些特工的指控几乎是肯定的因此，一种不同于针对 催化领域是迫切需要的。PPI制药公司将开发PLK1选择性非 ATP竞争性抑制剂作为有效的抗肿瘤治疗剂， 对常规激酶抑制剂有抗性的活性位点突变体。这些化合物将具有 作为具有降低肿瘤可能性的抗肿瘤剂的显著开发潜力 阻力和脱靶效应。

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.