Llauger Laura, He Huazhong, Kim Joungnam, Aguirre Julia, Rosen Neal, Peters Ulf, Davies Peter, Chiosis Gabriela
Department of Medicine and Program in Molecular Pharmacology and Chemistry, Memorial Sloan-Kettering Cancer Center, New York, New York 10021, USA.
J Med Chem. 2005 Apr 21;48(8):2892-905. doi: 10.1021/jm049012b.
Hsp90 is a chaperone protein with important roles in maintaining transformation and in elevating the survival and growth potential of cancer cells. Currently there is an increasing interest in developing inhibitors of this protein as anticancer therapeutics. One of such inhibitors, the purine-scaffold class, has been reported to be potent and selective against Hsp90 both in vitro and in vivo models of cancer. Here, a series of 8-arylsulfanyl, -sulfoxyl, and -sulfonyl adenine members of the purine class was synthesized and evaluated as inhibitors of the chaperone. The structure-activity relationship and selectivity for tumor Hsp90 of compounds within the series is presented. Our results suggest that 8-arylsulfanyl adenine derivatives are good inhibitors of chaperone activity, whereas oxidation of the sulfides to sulfoxides or sulfones leads to compounds of decreased activity. The study identifies derivative 11v as the most potent Hsp90 inhibitor of the purine-scaffold series published to date (EC(50) = 30 nM), and also as the compound of this class with highest selectivity for tumor vs normal cell Hsp90 (700 to 3000-fold). Most rewardingly, this work has allowed for the identification of Hsp90 inhibitors with selective affinities for Hsp90-client protein complexes, derivatives that may represent useful pharmacological tools in dissecting Hsp90-regulated processes.
热休克蛋白90（Hsp90）是一种伴侣蛋白，在维持癌细胞的转化以及提高其存活和生长潜力方面发挥着重要作用。目前，人们对开发这种蛋白的抑制剂作为抗癌治疗药物的兴趣与日俱增。其中一种抑制剂，嘌呤骨架类，据报道在癌症的体外和体内模型中对Hsp90都具有强效和选择性。在此，合成了一系列嘌呤类的8-芳基硫烷基、-亚砜基和-砜基腺嘌呤成员，并将其作为伴侣蛋白的抑制剂进行评估。展示了该系列化合物的构效关系以及对肿瘤Hsp90的选择性。我们的结果表明，8-芳基硫烷基腺嘌呤衍生物是伴侣蛋白活性的良好抑制剂，而硫化物氧化为亚砜或砜会导致活性降低的化合物。该研究确定衍生物11v是迄今为止报道的嘌呤骨架系列中最有效的Hsp90抑制剂（半数有效浓度（EC50）= 30 nM），也是该类化合物中对肿瘤与正常细胞Hsp90具有最高选择性的化合物（700至3000倍）。最值得庆幸的是，这项工作使得能够鉴定出对Hsp90-客户蛋白复合物具有选择性亲和力的Hsp90抑制剂，这些衍生物可能是剖析Hsp90调节过程中有用的药理学工具。
