Boyd Scott, Brookfield Joanna L, Critchlow Susan E, Cumming Iain A, Curtis Nicola J, Debreczeni Judit, Degorce Sébastien L, Donald Craig, Evans Nicola J, Groombridge Sam, Hopcroft Philip, Jones Neil P, Kettle Jason G, Lamont Scott, Lewis Hilary J, MacFaull Philip, McLoughlin Sheila B, Rigoreau Laurent J M, Smith James M, St-Gallay Steve, Stock Julie K, Turnbull Andrew P, Wheatley Edward R, Winter Jon, Wingfield Jonathan
†Oncology Innovative Medicines Unit, AstraZeneca, 35S47 Mereside, Alderley Park, Macclesfield, Cheshire SK10 4TG, United Kingdom.
‡CRT Discovery Laboratories, Jonas Webb Building (B910), Babraham Research Campus, Cambridge, CB22 3AT, United Kingdom.
J Med Chem. 2015 Apr 23;58(8):3611-25. doi: 10.1021/acs.jmedchem.5b00352. Epub 2015 Apr 13.
A weak screening hit with suboptimal physicochemical properties was optimized against PFKFB3 kinase using critical structure-guided insights. The resulting compounds demonstrated high selectivity over related PFKFB isoforms and modulation of the target in a cellular context. A selected example demonstrated exposure in animals following oral dosing. Examples from this series may serve as useful probes to understand the emerging biology of this metabolic target.
利用关键的结构导向见解，针对6-磷酸果糖-2-激酶/果糖-2,6-二磷酸酶3（PFKFB3）激酶对一种理化性质次优的筛选命中物进行了优化。所得化合物对相关的PFKFB同工型表现出高选择性，并在细胞环境中对靶点进行了调节。一个选定的例子显示了口服给药后在动物体内的暴露情况。该系列的例子可作为有用的探针，以了解这个代谢靶点的新生物学特性。
