The molecular chaperone heat shock protein 90 complex (Hsp90) is required for the conformational maturation and stability of a variety of key signaling proteins, including representatives of the ErbB family, AKT, Raf, p53, cdk4, etc.. These Hsp90 \#8220;clients\#8221; are involved in the pathways regulating proliferation and transformation of cancer cells. Geldanamycin derivatives, such as 17-allylamino-17-demethoxy-geldanamycin (17-AAG), exhibit potent anti-tumor activity against cancer cells and have entered clinical trials. Here we describe a novel class of small compounds from a pyrrolidine and isoindoline resorcinol amide series, PF-4470296 and PF-3823863 as two representatives. They are specific Hsp90 inhibitors able to induce Hsp90 client protein degradation, inhibit in vitro cell proliferation and transformation, and tumor growth of human melanoma cells in in vivo xenograft. Using these specific Hsp90 inhibitors, we demonstrated a difference in sensitivity in B-Raf protein degradation in human melanoma cells harboring WT vs. mutant B-Raf (V600E). PF-4470296 and PF-3823863 treatments induced B-Raf protein degradation with greater potency in mutant than in WT B-Raf containing cells but showed similar potency in other client protein degradation (such as AKT, Her2, and EGFR1). Both PF-4470296 and PF-3823863 inhibited cell proliferation and anchorage-independent growth in a variety of melanoma cell lines. PF-3823863 displayed greater metabolic stability and more favorable pharmacokinetics than PF-4470296. PF-3823863 induced tumor growth inhibition in the A2058 melanoma xenografts. Our results suggest that both PF-4470296 and PF-3823863 are potent and specific Hsp90 inhibitors and that PF-3823863 has a potential therapeutic advantage in the melanoma patients.

Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 4676.

100th AACR Annual Meeting-- Apr 18-22, 2009; Denver, CO

American Association for Cancer Research
2009