School of Engineering & Physical Sciences , Heriot-Watt University , Edinburgh EH14 4AS , U.K.
Strathclyde Institute of Pharmacy and Biomedical Sciences , University of Strathclyde , Glasgow G4 0RE , U.K.
J Med Chem. 2019 Apr 11;62(7):3658-3676. doi: 10.1021/acs.jmedchem.9b00162. Epub 2019 Mar 27.
Sphingosine kinase enzymes (SK1 and SK2) catalyze the conversion of sphingosine into sphingosine 1-phosphate and play a key role in lipid signaling and cellular responses. Mapping of isoform amino acid sequence differences for SK2 onto the recently available crystal structures of SK1 suggests that subtle structural differences exist in the foot of the lipid-binding "J-channel" in SK2, the structure of which has yet to be defined by structural biology techniques. We have probed these isoform differences with a ligand series derived from the potent SK1-selective inhibitor, PF-543. Here we show how it is possible, even with relatively conservative changes in compound structure, to systematically tune the activity profile of a ligand from ca. 100-fold SK1-selective inhibition, through equipotent SK1/SK2 inhibition, to reversed 100-fold SK2 selectivity, with retention of nanomolar potency.
鞘氨醇激酶酶（SK1 和 SK2）催化鞘氨醇转化为鞘氨醇 1-磷酸，并在脂质信号转导和细胞反应中发挥关键作用。将 SK2 的同工型氨基酸序列差异映射到最近获得的 SK1 晶体结构上表明，在 SK2 的脂质结合“J 通道”的足部存在细微的结构差异，其结构尚未通过结构生物学技术来定义。我们使用源自强效 SK1 选择性抑制剂 PF-543 的配体系列来探测这些同工型差异。在这里，我们展示了即使在化合物结构相对保守的情况下，如何系统地调整配体的活性谱，使配体的活性从约 100 倍的 SK1 选择性抑制，通过等效的 SK1/SK2 抑制，到 100 倍的 SK2 选择性逆转，同时保持纳米摩尔效力。
