Emerging Raf inhibitors

Abstract

Various Raf inhibitors have been developed and are being clinically used to treat patients with melanoma, thyroid, hepatocellular and renal cell cancers. Some 'Raf-kinase inhibitors' affect other kinases which are also expressed on malignant cells; yet, these inhibitors have proven useful in the therapy of certain cancer patients. Other more recently developed Raf specific inhibitors have shown success in the treatment of tumors bearing Raf mutations. The development of Raf inhibitors has significantly advanced cancer therapy in the past decade.

Roles of the Ras/Raf/MEK/ERK pathway in leukemia therapy

“…It has been known for quite some time now, that treatment with certain inhibitors (for example, Raf inhibitors), can result in hyper-activation of wildtype (WT) Raf. 8,[146][147][148] It has recently become clear that it will be essential to determine the genetic status at both BRAF and RAS before treatment with B-Raf selective inhibitors proceeds. 149 Class I B-Raf inhibitors (active conformation inhibitors) such as PLX4720 and 885-A (a close analog of SB590885) will inhibit BRAF mutants, however, these ATP-competitive B-Raf inhibitors will not inhibit WT BRAF or mutant RAS.…”

“…[1][2][3][4][5][6][7][8][9][10][11][12] Mutations can occur in the genes encoding pathway constituents (for example, Ras and Raf), upstream receptors (for example, Kit, Fms and Fms-like tyrosine kinase (Flt)-3) or chromosomal translocations (for example, BCR-ABL and TEL-platelet-derived growth factor receptor (PDGFR)), which activate this pathway. Chemotherapeutic drugs frequently used in leukemia therapy often activate this pathway.…”

“…1,2 This pathway relays this information through interactions with various other proteins to the nucleus to control gene expression. [1][2][3][4][5][6][7][8][9][10][11][12] This review will discuss how these pathways may be aberrantly regulated in leukemia and contribute to therapeutic sensitivity/resistance and in some cases poor prognosis. [4][5]13 Inhibition of Ras (or Ras-related molecules), Raf, MEK and ERK may prove useful in leukemia treatment.…”

Melanoma Cell Signalling: Looking Beyond RAS-RAF-MEK

“…It has also been reported that the RAS mutational status did not correlate with their sensitivity to FTI which suggests that other signalling molecules are affected by these inhibitors (Niessner et al, 2011;Sebti and Hamilton, 1997;Sepp-Lorenzino et al, 1995). Although, FTI are beneficial in joint therapies to overcome drug resistance, its non-specificity to N-RAS needs to be addressed (Flaherty, 2006;Held et al, 2011;McCubrey et al, 2009). Furthermore, FTI may also be ineffective if RAS downstream targets acquire oncogenic mutations.…”

An Activating Transcription Factor 5-Mediated Survival Pathway as a Target for Cancer Therapy

“…One of these inhibitors, sorafenib, is a multi-kinase inhibitor whose strongest activity is against RAF kinases and has been used to treat several different types of cancers [16,17]. Sorafenib inhibits the growth of human malignant glioma xenografts in mice, which suggests it may also be used to treat malignant glioma [11].…”