Park Hwangseo, Jeon Jinwon, Kim Kewon, Choi Soyeon, Hong Sungwoo
Department of Bioscience and Biotechnology and Institute of Anticancer Medicine Development, Sejong University, 209 Neungdong-ro, Kwangjin-gu, Seoul 05006, Korea.
Center for Catalytic Hydrocarbon Functionalizations, Institute for Basic Science (IBS), Daejeon 34141, Korea.
Pharmaceuticals (Basel). 2021 Mar 18;14(3):275. doi: 10.3390/ph14030275.
the proviral insertion site of Moloney murine leukemia (PIM) 1 kinase has served as a therapeutic target for various human cancers due to the enhancement of cell proliferation and the inhibition of apoptosis.
to identify effective PIM1 kinase inhibitors, structure-based virtual screening of natural products of plant origin and de novo design were carried out using the protein-ligand binding free energy function improved by introducing an adequate dehydration energy term.
as a consequence of subsequent enzyme inhibition assays, four classes of PIM1 kinase inhibitors were discovered, with the biochemical potency ranging from low-micromolar to sub-micromolar levels. The results of extensive docking simulations showed that the inhibitory activity stemmed from the formation of multiple hydrogen bonds in combination with hydrophobic interactions in the ATP-binding site. Optimization of the biochemical potency by chemical modifications of the 2-benzylidenebenzofuran-3(2)-one scaffold led to the discovery of several nanomolar inhibitors with antiproliferative activities against human breast cancer cell lines.
these new PIM1 kinase inhibitors are anticipated to serve as a new starting point for the development of anticancer medicine.
莫洛尼鼠白血病（PIM）1激酶的前病毒插入位点因能促进细胞增殖和抑制细胞凋亡，已成为多种人类癌症的治疗靶点。
为了鉴定有效的PIM1激酶抑制剂，利用通过引入适当脱水能项改进的蛋白质-配体结合自由能函数，对植物源天然产物进行基于结构的虚拟筛选和从头设计。
后续酶抑制试验的结果发现了四类PIM1激酶抑制剂，其生化活性范围从低微摩尔到亚微摩尔水平。广泛的对接模拟结果表明，抑制活性源于在ATP结合位点形成多个氢键并伴有疏水相互作用。通过对2-亚苄基苯并呋喃-3(2)-酮支架进行化学修饰来优化生化活性，从而发现了几种对人乳腺癌细胞系具有抗增殖活性的纳摩尔抑制剂。
这些新型PIM1激酶抑制剂有望成为抗癌药物开发的新起点。
