PF-04880594

PF-04880594 is a selective inhibitor of B-Raf, B-RafV599E and c-Raf with IC50 value of 0.19 nM, 0.13 nM and 0.39 nM, respectively [1].

Raf is a serine/threonine protein kinase and plays an important role in the MAPK/ERK signaling pathway. It has been revealed that Raf involves in cancers and developmental syndromes and its inhibitors are regarded as a promising target for cancer treatment [2, 3].

PF-04880594 is a potent Raf inhibitor. When tested with GTL16 and GTL16 resistant cell clones, PF-04880594 treatment significantly decreased cell viability and ERK activity [2]. In 3D culture model of RHE cells (histologic similar to human epidermal lasers), PF-04880594 treatment (62.5 nmol/L, 2 d) significantly induced necrosis with ghost cells accounting for nearly 50% to 60% of the culture thickness via inducing p-ERK expression level [3].

Treated nude mice model with PF-04880594 (10-40 mg/kg, twice daily for 3 weeks) and then mice were sacrificed for further study. The results revealed that PF-04880594 treatment induced ERK phosphorylation and B-Raf-c-Raf dimerization in multiple epithelial tissues which phenomenon could be attenuated by PD-0325901 [3].

References:
[1].  Palmer C, Cui J, Deal J, Gu D, Guo C, Kephart S, et al. Discovery of potent, selective inhibitors of mutant B-Raf. (Abstract # MEDI-251). Abstracts of Papers, 242nd ACS National Meeting & Exposition 2011.
[2].  Lee, N. V. Lira, M. E. Pavlicek, A., et al. A novel SND1-BRAF fusion confers resistance to c-Met inhibitor PF-04217903 in GTL16 cells through [corrected] MAPK activation [J]. PLoS One, 2012, 7(6): e39653.
[3].  Vince R. Torti, Donald Wojciechowicz, Wenyue Hu, et al. Epithelial Tissue Hyperplasia Induced by the RAF Inhibitor PF-04880594 Is Attenuated by a Clinically Well-Tolerated Dose of the MEK Inhibitor PD-0325901 [J]. Mol Cancer Ther, 2012, 11(10):2274-2283.

Epithelial tissue hyperplasia induced by the RAF inhibitor PF-04880594 is attenuated by a clinically well-tolerated dose of the MEK inhibitor PD-0325901.[Pubmed:22752429]

Mol Cancer Ther. 2012 Oct;11(10):2274-83.

Clinical trials of selective RAF inhibitors in patients with melanoma tumors harboring activated BRAFV600E have produced very promising results, and a RAF inhibitor has been approved for treatment of advanced melanoma. However, about a third of patients developed resectable skin tumors during the course of trials. This is likely related to observations that RAF inhibitors activate extracellular signal-regulated kinase (ERK) signaling, stimulate proliferation, and induce epithelial hyperplasia in preclinical models. Because these findings raise safety concerns about RAF inhibitor development, we further investigated the underlying mechanisms. We showed that the RAF inhibitor PF-04880594 induces ERK phosphorylation and RAF dimerization in those epithelial tissues that undergo hyperplasia. Hyperplasia and ERK hyperphosphorylation are prevented by treatment with the mitogen-activated protein/extracellular signal-regulated kinase (MEK) inhibitor PD-0325901 at exposures that extrapolate to clinically well-tolerated doses. To facilitate mechanistic and toxicologic studies, we developed a three-dimensional cell culture model of epithelial layering that recapitulated the RAF inhibitor-induced hyperplasia and reversal by MEK inhibitor in vitro. We also showed that PF-04880594 stimulates production of the inflammatory cytokine interleukin 8 in HL-60 cells, suggesting a possible mechanism for the skin flushing observed in dogs. The complete inhibition of hyperplasia by MEK inhibitor in epithelial tissues does not seem to reduce RAF inhibitor efficacy and, in fact, allows doubling of the PF-04880594 dose without toxicity usually associated with such doses. These findings indicated that combination treatment with MEK inhibitors might greatly increase the safety and therapeutic index of RAF inhibitors for the treatment of melanoma and other cancers.

Vemurafenib (PLX4032, RG7204) is a novel and potent inhibitor of B-RafV600E with IC50 of 31 nM in cell-free assay. 10-fold selective for B-RafV600E over wild-type B-Raf in enzymatic assays and the cellular selectivity can exceed 100-fold.

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