醌类作为新型PIM1激酶抑制剂的鉴定。
Identification of quinones as novel PIM1 kinase inhibitors.
作者信息
Schroeder Richard L, Goyal Navneet, Bratton Melyssa, Townley Ian, Pham Nancy A, Tram Phan, Stone Treasure, Geathers Jasmine, Nguyen Kathy, Sridhar Jayalakshmi
机构信息
Department of Chemistry, Xavier University of Louisiana, 1, Drexel Dr., New Orleans, LA 70125, USA.
Cell and Molecular Biology Core Facility, Xavier University of Louisiana, New Orleans, LA 70125, USA.
出版信息
Bioorg Med Chem Lett. 2016 Jul 1;26(13):3187-3191. doi: 10.1016/j.bmcl.2016.04.079. Epub 2016 Apr 28.
PIM1 is a proto-oncogene encoding the serine/threonine PIM1 kinase. PIM1 kinase plays important roles in regulating aspects of cell cycle progression, apoptosis resistance, and has been implicated in the development of such malignancies as prostate cancer and acute myeloid leukemia among others. Knockout of PIM1 kinase in mice has been shown to be non-lethal without any obvious phenotypic changes, making it an attractive therapeutic target. Our investigation of anthraquinones as kinase inhibitors revealed a series of quinone analogs showing high selectivity for inhibition of the PIM kinases. Molecular modeling studies were used to identify key interactions and binding poses of these compounds within the PIM1 binding pocket. Compounds 1, 4, 7 and 9 inhibited the growth of DU-145 prostate cancer cell lines with a potency of 8.21μM, 4.06μM, 3.21μM and 2.02μM.
PIM1是一种原癌基因，编码丝氨酸/苏氨酸PIM1激酶。PIM1激酶在调节细胞周期进程、抗凋亡等方面发挥重要作用，并且与前列腺癌和急性髓系白血病等恶性肿瘤的发生有关。已证明敲除小鼠体内的PIM1激酶不会致死，也不会产生任何明显的表型变化，这使其成为一个有吸引力的治疗靶点。我们对蒽醌类作为激酶抑制剂的研究发现了一系列对PIM激酶抑制具有高选择性的醌类似物。分子建模研究用于确定这些化合物在PIM1结合口袋内的关键相互作用和结合构象。化合物1、4、7和9对DU - 145前列腺癌细胞系生长的抑制效力分别为8.21μM、4.06μM、3.21μM和2.02μM。
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