Li Xiaokai, Srinivasan Sharan R, Connarn Jamie, Ahmad Atta, Young Zapporah T, Kabza Adam M, Zuiderweg Erik R P, Sun Duxin, Gestwicki Jason E
Department of Pharmaceutical Chemistry, University of California at San Francisco, San Francisco, CA 94158.
ACS Med Chem Lett. 2013 Nov 14;4(11):1042-7. doi: 10.1021/ml400204n.
The rhodacyanine, MKT-077, has anti-proliferative activity against cancer cell lines through its ability to inhibit members of the heat shock protein 70 (Hsp70) family of molecular chaperones. However, MKT-077 is rapidly metabolized, which limits its use as either a chemical probe or potential therapeutic. We report the synthesis and characterization of MKT-077 analogs designed for greater stability. The most potent molecules, such as (JG-98), were at least 3-fold more active than MKT-077 against the breast cancer cell lines MDA-MB-231 and MCF-7 (EC values of 0.4 ± 0.03 μM and 0.7 ± 0.2 μM, respectively). The analogs modestly destabilized the chaperone "clients", Akt1 and Raf1, and induced apoptosis in these cells. Further, the microsomal half-life of JG-98 was improved at least 7-fold (t = 37 min) compared to MKT-077 (t < 5 min). Finally, NMR titration experiments suggested that these analogs bind an allosteric site that is known to accommodate MKT-077. These studies advance MKT-077 analogs as chemical probes for studying Hsp70's roles in cancer.
玫红花青素MKT-077通过抑制分子伴侣热休克蛋白70（Hsp70）家族成员，对癌细胞系具有抗增殖活性。然而，MKT-077代谢迅速，这限制了其作为化学探针或潜在治疗药物的应用。我们报道了为提高稳定性而设计的MKT-077类似物的合成与表征。最有效的分子，如（JG-98），对乳腺癌细胞系MDA-MB-231和MCF-7的活性比MKT-077至少高3倍（EC值分别为0.4±0.03μM和0.7±0.2μM）。这些类似物适度地使分子伴侣“客户”Akt1和Raf1不稳定，并在这些细胞中诱导凋亡。此外，与MKT-077（t<5分钟）相比，JG-98的微粒体半衰期至少提高了7倍（t=37分钟）。最后，核磁共振滴定实验表明，这些类似物结合了一个已知可容纳MKT-077的变构位点。这些研究推动了MKT-077类似物作为研究Hsp70在癌症中作用的化学探针的发展。
