Department of Pharmaceutical Chemistry, ISF College of Pharmacy, Moga, India.
Department of Pharmaceutical Chemistry, ISF College of Pharmacy, Moga, India.
Bioorg Chem. 2021 Sep;114:105161. doi: 10.1016/j.bioorg.2021.105161. Epub 2021 Jul 13.
The mitogen activated protein kinase (MAPK) belongs to group of kinase that links the extracellular stimuli to intracellular response. The MAPK signalling pathway (RAS-RAF-MEK-ERK) involved in different pathological conditions like cancer, caused due to genetic or any other factor such as physical or environmental. Many studies have been conducted on the pathological view of MAPK cascade and its associated element like RAS, RAF, MEK, ERK or its isoforms, and still the research is going on particularly with respect to its activation, regulation and inhibition. The MAPK signalling pathway has become the area of research to identify new target for the management of cancer. A number of heterocyclics are key to fight with the cancer associated with these enzymes thus give some hope in the management of cancer by inhibiting MAPK cascade. In the present article, we have focussed on MAPK signalling pathway and role of different heterocyclic scaffolds bearing nitrogen, sulphur and oxygen and about their potential to block MAPK signalling pathway. The heterocyclics are gaining importance due to high potency and selectivity with less off-target effects against different targets involved in the MAPK signalling pathway. We have tried to cover recent advancements in the MAPK signalling pathway inhibitors with an aim to get better understanding of the mechanism of action of the compounds. Several compounds in the preclinical and clinical studies have been thoroughly dealt with. In addition to the synthetic compounds, a significant number of natural products containing heterocyclic moieties as MAPK signalling pathway inhibitors have been put together. The structure activity relationship along with docking studies have been discussed to apprehend the mechanistic studies of various compounds that will ultimately help to design and develop more MAPK signalling pathway inhibitors.
丝裂原活化蛋白激酶（MAPK）属于激酶家族，可将细胞外刺激与细胞内反应联系起来。MAPK 信号通路（RAS-RAF-MEK-ERK）参与了多种病理情况，如癌症，这些癌症是由遗传或其他因素（如物理或环境）引起的。许多研究已经针对 MAPK 级联及其相关元件（如 RAS、RAF、MEK、ERK 或其同工酶）的病理观点进行了研究，并且仍在继续研究，特别是针对其激活、调节和抑制。MAPK 信号通路已成为研究的领域，以确定癌症管理的新靶标。许多杂环化合物是与这些酶相关的癌症的关键，因此通过抑制 MAPK 级联提供了一些治疗癌症的希望。在本文中，我们重点介绍了 MAPK 信号通路和不同杂环支架（含氮、硫和氧）的作用，以及它们在阻断 MAPK 信号通路方面的潜力。杂环化合物由于对 MAPK 信号通路中涉及的不同靶标具有高活性和选择性，且脱靶效应较小，因此变得越来越重要。我们试图涵盖 MAPK 信号通路抑制剂的最新进展，以期更好地了解化合物的作用机制。已经彻底研究了临床前和临床研究中的几种化合物。除了合成化合物外，还将大量含有杂环部分的天然产物作为 MAPK 信号通路抑制剂进行了组合。讨论了结构活性关系和对接研究，以了解各种化合物的机制研究，这最终将有助于设计和开发更多的 MAPK 信号通路抑制剂。
