Novel small molecule Raf kinase inhibitors for targeted cancer therapeutics

@article{Kim2012NovelSM,
  title={Novel small molecule Raf kinase inhibitors for targeted cancer therapeutics},
  author={Do-Hee Kim and Taebo Sim},
  journal={Archives of Pharmacal Research},
  year={2012},
  volume={35},
  pages={605-615}
}
  • Do-Hee Kim, T. Sim
  • Published 3 May 2012
  • Biology, Chemistry
  • Archives of Pharmacal Research
AbstactAberrant activation of Raf signaling pathway is frequently found in various human tumors, it has been considered as distinct and promising molecular target for cancer therapeutics. B-Raf is most attractive drug target out of three Raf isoforms (A-Raf, B-Raf and C-Raf) because it exhibits high kinase activity due to frequent mutations in human tumors. However, most recently, it has been reported that Raf isoforms show the cross-activation in the presence of specific B-Raf inhibitors… 

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References

SHOWING 1-10 OF 71 REFERENCES

Discovery of a selective inhibitor of oncogenic B-Raf kinase with potent antimelanoma activity

PLX4720, a 7-azaindole derivative that inhibits B-RafV600E with an IC50 of 13 nM, defines a class of kinase inhibitor with marked selectivity in both biochemical and cellular assays and represents the entire discovery process from initial identification through structural and biological studies in animal models to a promising therapeutic for testing in cancer patients bearing B- RafV 600E-driven tumors.

Selective Raf inhibition in cancer therapy

The mode of action of Raf kinase family activities and protein interactions suggest specific approaches to inhibiting Raf, and the set of drugs, antisense reagents and antibodies available or in development for therapeutically targeting Raf or Raf-related proteins is summarized.

Clinical efficacy of a RAF inhibitor needs broad target blockade in BRAF-mutant melanoma

The structure-guided discovery of PLX4032 (RG7204), a potent inhibitor of oncogenic B-RAF kinase activity, and a remarkably high 81% response rate in metastatic melanoma patients treated at an oral dose of 960 mg twice daily are described, demonstrating that BRAF-mutant melanomas are highly dependent on B- RAF kinases activity.

Antitumor efficacy of the novel RAF inhibitor GDC-0879 is predicted by BRAFV600E mutational status and sustained extracellular signal-regulated kinase/mitogen-activated protein kinase pathway suppression.

The biological properties of GDC-0879, a highly selective, potent, and orally bioavailable RAF small-molecule inhibitor, are reported and the molecular determinants for antitumor efficacy resulting from RAF pathway inhibition are increased and have implications for therapeutic intervention in the clinic.

Elevated CRAF as a potential mechanism of acquired resistance to BRAF inhibition in melanoma.

To anticipate potential mechanisms of acquired resistance to RAF inhibitors during the course of treatment, drug-resistant clones are established from a human melanoma-derived cell line harboring the recurrent V600E activating BRAF mutation, which exhibits exquisite sensitivity to AZ628, a selective RAF kinase inhibitor.

B-RAF is a therapeutic target in melanoma

It is demonstrated that oncogenic B-RAF activates ERK signalling, induces proliferation and protects cells from apoptosis, demonstrating that it is an important therapeutic target and thus provides novel strategies for clinical management of melanoma and other cancers.

BRAF as therapeutic target in melanoma.

Design and discovery of small molecules targeting raf-1 kinase.

The medicinal chemistry development of ureas as highly potent inhibitors of Raf-1 kinase is summarized, which culminated in the identification of the clinical candidate BAY 43-9006, currently undergoing Phase I clinical trials.

COT/MAP3K8 drives resistance to RAF inhibition through MAP kinase pathway reactivation

Together, these results provide new insights into resistance mechanisms involving the MAPK pathway and articulate an integrative approach through which high-throughput functional screens may inform the development of novel therapeutic strategies.
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