Ge Jie, Normant Emmanuel, Porter James R, Ali Janid A, Dembski Marlene S, Gao Yun, Georges Asimina T, Grenier Louis, Pak Roger H, Patterson Jon, Sydor Jens R, Tibbitts Thomas T, Tong Jeffrey K, Adams Julian, Palombella Vito J
Infinity Pharmaceuticals, Inc., 780 Memorial Drive, Cambridge, Massachusetts 02139, USA.
J Med Chem. 2006 Jul 27;49(15):4606-15. doi: 10.1021/jm0603116.
17-Allylamino-17-demethoxygeldanamycin (17-AAG)1 is a semisynthetic inhibitor of the 90 kDa heat shock protein (Hsp90) currently in clinical trials for the treatment of cancer. However, 17-AAG faces challenging formulation issues due to its poor solubility. Here we report the synthesis and evaluation of a highly soluble hydroquinone hydrochloride derivative of 17-AAG, 1a (IPI-504), and several of the physiological metabolites. These compounds show comparable binding affinity to human Hsp90 and its endoplasmic reticulum (ER) homologue, the 94 kDa glucose regulated protein (Grp94). Furthermore, the compounds inhibit the growth of the human cancer cell lines SKBR3 and SKOV3, which overexpress Hsp90 client protein Her2, and cause down-regulation of Her2 as well as induction of Hsp70 consistent with Hsp90 inhibition. There is a clear correlation between the measured binding affinity of the compounds and their cellular activities. Upon the basis of its potent activity against Hsp90 and a significant improvement in solubility, 1a is currently under evaluation in Phase I clinical trials for cancer.
17-烯丙基氨基-17-去甲氧基格尔德霉素（17-AAG）1是一种90 kDa热休克蛋白（Hsp90）的半合成抑制剂，目前正处于治疗癌症的临床试验阶段。然而，由于其溶解性差，17-AAG面临着具有挑战性的制剂问题。在此，我们报告了17-AAG的一种高溶解性对苯二酚盐酸盐衍生物1a（IPI-504）以及几种生理代谢物的合成与评估。这些化合物对人Hsp90及其内质网（ER）同源物94 kDa葡萄糖调节蛋白（Grp94）表现出相当的结合亲和力。此外，这些化合物抑制过表达Hsp90客户蛋白Her2的人癌细胞系SKBR3和SKOV3的生长，并导致Her2下调以及与Hsp90抑制一致的Hsp70诱导。化合物的实测结合亲和力与其细胞活性之间存在明显的相关性。基于其对Hsp90的强效活性以及溶解性的显著改善，1a目前正在进行癌症的I期临床试验评估。
