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Abstract: Hsp90 is required for conformational maturation and stability of numerous key signaling proteins (clients) involved in cell proliferation and transformation. Here we describe two novel Hsp90 inhibitors, PF-4470296 and PF-3823863, demonstrate a differential sensitivity in B-Raf mutant (V600E) versus wild-type protein degradation. These two inhibitors inhibit proliferation and anchorage-independent growth, and abolish in vivo xenograft tumor growth in melanoma cells regardless of B-Raf mutation status. Mutant B-Raf protein and other Hsp90 clients, such as cMet, ErbB2, C-Raf, and AKT, are degraded in cells and xenograft tumors. Our results indicate that Hsp90 inhibitors induce anti-tumor activity in melanoma cells and are likely to show therapeutic benefit in melanoma patients by collaboratively targeting multiple pathways. [ABSTRACT FROM AUTHOR]