Targeting Mitogen-Activated Protein Kinase-Activated Protein Kinase 2 (MAPKAPK2, MK2): Medicinal Chemistry Efforts To Lead Small Molecule Inhibitors to Clinical Trials.
Targeting Mitogen-Activated Protein Kinase-Activated Protein Kinase 2 (MAPKAPK2, MK2): Medicinal Chemistry Efforts To Lead Small Molecule Inhibitors to Clinical Trials.
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DOI：
10.1021/acs.jmedchem.5b01457
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发表时间：
2016-04-28
影响因子：
7.3
通讯作者：
Manetti F
中科院分区：
文献类型：
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作者：
Fiore M;Forli S;Manetti F
p38/MAPK活化激酶2（MAPK-activated kinase 2，MK2）通路参与一系列病理状态（炎症、疾病和转移）和抗肿瘤药物的耐药机制。没有一种p38抑制剂进入高级临床试验，因为它们有不必要的全身副作用。因此，MK2被确定为阻断该途径的替代靶标，但避免了p38抑制的副作用。然而，ATP竞争性MK2抑制剂的溶解度低，细胞渗透性差，缺乏激酶的选择性。幸运的是，已经发现了MK2的非ATP竞争性抑制剂，可以避免选择性问题。与ATP竞争性抑制剂相比，这些化合物显示出在较低浓度下有效的额外优势。因此，尽管在开发这些抑制剂的过程中遇到了重大困难，但MK2仍然被认为是治疗炎症和相关疾病、预防肿瘤转移以及增加肿瘤对化疗药物的敏感性的有吸引力的靶标。
The p38/MAPK-activated kinase 2 (MK2) pathway is involved in a series of pathological conditions (inflammation diseases and metastasis) and in the resistance mechanism to antitumor agents. None of the p38 inhibitors entered advanced clinical trials because of their unwanted systemic side effects. For this reason, MK2 was identified as an alternative target to block the pathway, but avoiding the side effects of p38 inhibition. However, ATP-competitive MK2 inhibitors suffered from low solubility, poor cell permeability, and scarce kinase selectivity. Fortunately, non-ATP-competitive inhibitors of MK2 have been already discovered that allowed circumventing the selectivity issue. These compounds showed the additional advantage to be effective at lower concentrations in comparison to the ATP-competitive inhibitors. Therefore, although the significant difficulties encountered during the development of these inhibitors, MK2 is still considered as an attractive target to treat inflammation and related diseases, to prevent tumor metastasis, and to increase tumor sensitivity to chemotherapeutics.