title: Analogs of the Allosteric Heat Shock Protein 70 (Hsp70) Inhibitor, MKT-077, as Anti-Cancer Agents.
abstract: 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 as30(JG-98), were at least 3-fold more active than MKT-077 against the breast cancer cell lines MDA-MB-231 and MCF-7 (EC50values 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 (t1/2= 37 min) compared to MKT-077 (t1/2< 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.
authors: Department of Pharmaceutical Chemistry, University of California at San Francisco, San Francisco, CA 94158.
authors: Xiaokai
authors: X
authors: Li
authors: Sharan R
authors: SR
authors: Srinivasan
authors: Jamie
authors: J
authors: Connarn
authors: Atta
authors: A
authors: Ahmad
authors: Zapporah T
authors: ZT
authors: Young
authors: Adam M
authors: AM
authors: Kabza
authors: Erik R P
authors: ER
authors: Zuiderweg
authors: Duxin
authors: D
authors: Sun
authors: Jason E
authors: JE
authors: Gestwicki
keywords: Hsp90; breast cancer; mortalin; p53; proteostasis