Ward Richard A, Colclough Nicola, Challinor Mairi, Debreczeni Judit E, Eckersley Kay, Fairley Gary, Feron Lyman, Flemington Vikki, Graham Mark A, Greenwood Ryan, Hopcroft Philip, Howard Tina D, James Michael, Jones Clifford D, Jones Christopher R, Renshaw Jonathan, Roberts Karen, Snow Lindsay, Tonge Michael, Yeung Kay
J Med Chem. 2015 Jun 11;58(11):4790-801. doi: 10.1021/acs.jmedchem.5b00466. Epub 2015 May 28.
The RAS/RAF/MEK/ERK signaling pathway has been targeted with a number of small molecule inhibitors in oncology clinical development across multiple disease indications. Importantly, cell lines with acquired resistance to B-RAF and MEK inhibitors have been shown to maintain sensitivity to ERK1/2 inhibition by small molecule inhibitors. There are a number of selective, noncovalent ERK1/2 inhibitors reported along with the promiscuous hypothemycin (and related analogues) that act via a covalent mechanism of action. This article reports the identification of multiple series of highly selective covalent ERK1/2 inhibitors informed by structure-based drug design (SBDD). As a starting point for these covalent inhibitors, reported ERK1/2 inhibitors and a chemical series identified via high-throughput screening were exploited. These approaches resulted in the identification of selective covalent tool compounds for potential in vitro and in vivo studies to assess the risks and or benefits of targeting this pathway through such a mechanism of action.
在多种疾病适应症的肿瘤学临床开发中，RAS/RAF/MEK/ERK信号通路已成为多种小分子抑制剂的作用靶点。重要的是，对B-RAF和MEK抑制剂产生获得性耐药的细胞系已被证明对小分子抑制剂抑制ERK1/2仍保持敏感性。已报道了许多选择性非共价ERK1/2抑制剂以及通过共价作用机制发挥作用的混杂霉素（及相关类似物）。本文报道了基于结构的药物设计（SBDD）指导下的多个系列高选择性共价ERK1/2抑制剂的鉴定。作为这些共价抑制剂的起点，已报道的ERK1/2抑制剂以及通过高通量筛选确定的一个化学系列被加以利用。这些方法导致鉴定出选择性共价工具化合物，用于潜在的体外和体内研究，以评估通过这种作用机制靶向该通路的风险和/或益处。
