Advances in the research and development of B-Raf inhibitors

DONG Gaochao; ZHOU Xiang; TANG Weifang; LU Tao

doi:10.11665/j.issn.1000-5048.20140101

Journal of China Pharmaceutical University > 2014 > 45(1): 1-9. > DOI: 10.11665/j.issn.1000-5048.20140101

DONG Gaochao, ZHOU Xiang, TANG Weifang, LU Tao. Advances in the research and development of B-Raf inhibitors[J]. Journal of China Pharmaceutical University, 2014, 45(1): 1-9. DOI: 10.11665/j.issn.1000-5048.20140101

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Advances in the research and development of B-Raf inhibitors

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Abstract

Oncogenic B-Raf has been identified in a variety of cancers with high incidence, especially in malignant melanoma and thyroid cancer. In 2011, selective B-Raf kinase inhibitor vemurafenib was approved by FDA, and that stimulated increasing interest in B-Raf inhibitors as anticancer agents. Through analyzing the X-ray crystal structure of vemurafenib bound to B-Raf kinase, new classification of B-Raf kinase inhibitors was proposed. This review focuses on diverse small-molecule inhibitors of B-Raf kinase published in protein data bank(PDB)from 2011 to date based on the new classification. The binding modes and structure-activity relationship(SAR)as well as the future development of these inhibitors are discussed.
- B-Raf kinase,
- B-Raf kinase inhibitor,
- classification

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[1]	Howe LR, Leevers SJ, Gómez N, et al. Activation of the MAP kinase pathway by the protein kinase raf[J].Cell,1992,71(2):335-342.
[2]	Davies H,Bignell GR,Cox C,et al.Mutations of the BRAF gene in human cancer[J].Nature,2002,417(6 892):949-954.
[3]	Wan PTC,Garnett MJ,Roe SM,et al.Mechanism of activation of the RAF-ERK signaling pathway by oncogenic mutations of B-RAF[J].Cell,2004,116(6):855-867.
[4]	Roskoski R Jr.RAF protein-serine/threonine kinases:structure and regulation[J].Biochem Biophys Res Commun,2010,399(3):313-317.
[5]	van Linden OP,Kooistra AJ,Leurs R,et al.KLIFS:A knowledge-based structural database to navigate kinase-ligand interaction space[J].J Med Chem,2013,10.1021/jm400378w.
[6]	Li HF,Chen Y,Rao SS,et al.Recent advances in the research and development of B-Raf inhibitors[J].Curr Med Chem,2010,17(16):1 618-1 634.
[7]	King AJ, Patrick DR, Batorsky RS, et al. Demonstration of a genetic therapeutic index for tumors expressing oncogenic BRAF by the kinase inhibitor SB-590885[J].Cancer Res,2006,66(23):11 100-11 105.
[8]	Wilhelm S,Carter C,Lynch M,et al.Discovery and development of sorafenib:a multikinase inhibitor for treating cancer[J].Nat Rev Drug Discov,2006,5(10):835-844.
[9]	Bollag G, Tsai J, Zhang J, et al. Vemurafenib: the first drug approved for BRAF-mutant cancer[J].Nat Rev Drug Discov,2012,11(11):873-886.
[10]	Wang X and Kim J Conformation-specific effects of Raf kinase inhibitors[J].J Med Chem,2012,55(17):7 332-7 341.
[11]	Buckmelter AJ,Ren L,Laird ER,et al.The discovery of furo [2,3-c]pyridine-based indanone oximes as potent and selective B-Raf inhibitors[J].Bioorg Med Chem Lett,2011,21(4):1 248-1 252.
[12]	Dalvie DK,Kalgutkar AS,Khojasteh-Bakht SC,et al.Biotransformation reactions of five-membered aromatic heterocyclic rings[J].Chem Res Toxicol,2002,15(3):269-299.
[13]	Ren L,Wenglowsky S,Miknis G,et al.Non-oxime inhibitors of B-Raf(V600E)kinase[J].Bioorg Med Chem Lett,2011,21(4):1 243-1 247.
[14]	Newhouse BJ,Hansen JD,Grina J,et al.Non-oxime pyrazole based inhibitors of B-Raf kinase[J].Bioorg Med Chem Lett,2011,21(11):3 488-3 492.
[15]	Vasbinder MM,Aquila B,Augustin M,et al.Discovery and optimization of a novel series of potent mutant B-Raf(V600E)selective kinase inhibitors[J].J Med Chem,2013,56(5):1 996-2 015.
[16]	Liao JJ.Molecular recognition of protein kinase binding pockets for design of potent and selective kinase inhibitors[J].J Med Chem,2007,50(3):409-424.
[17]	Eisen T,Ahmad T,Flaherty KT,et al.Sorafenib in advanced melanoma:a phase II randomised discontinuation trial analysis[J].Br J Cancer,2006,95(5):581-586.
[18]	Okaniwa M, Hirose M, Imada T, et al. Design and synthesis of novel DFG-out RAF/vascular endothelial growth factor receptor 2(VEGFR2)inhibitors.1.Exploration of [5,6]-fused bicyclic scaffolds[J].J Med Chem,2012,55(7):3 452-3 478.
[19]	Ishikawa M,Hashimoto Y.Improvement in aqueous solubility in small molecule drug discovery programs by disruption of molecular planarity and symmetry[J].J Med Chem,2011,54(6):1 539-1 554.
[20]	Hirose M,Okaniwa M,Miyazaki T,et al.Design and synthesis of novel DFG-out RAF/vascular endothelial growth factor receptor 2(VEGFR2)inhibitors:3.Evaluation of 5-amino-linked thiazolo[5,4-d]pyrimidine and thiazolo[5,4-b]pyridine derivatives[J].Bioorg Med Chem,2012,20(18):5 600-5 615.
[21]	Okaniwa M,Hirose M,Arita T,et al.Discovery of a selective kinase inhibitor(TAK-632)targeting pan-RAF inhibition:design,synthesis,and biological evaluation of C-7-substituted 1,3-benzothiazole derivatives[J].J Med Chem,2013,56(16):6 478-6 494.
[22]	Gould AE,Adams R,Adhikari S,et al.Design and optimization of potent and orally bioavailable tetrahydronaphthalene Raf inhibitors[J].J Med Chem,2011,54(6):1 836-1 846.
[23]	Tsai J,Lee JT,Wang W,et al.Discovery of a selective inhibitor of oncogenic B-Raf kinase with potent antimelanoma activity[J].Proc Natl Acad Sci U S A,2008,105(8):3 041-3 046.
[24]	Wenglowsky S,Ren L,Ahrendt KA,et al.Pyrazolopyridine inhi-bitors of B-RafV600E.Part 1:the development of selective,orally bioavailable,and efficacious inhibitors[J].ACS Med Chem Lett,2011,2(5):342-347.
[25]	Wenglowsky S,Ahrendt KA,Buckmelter AJ,et al.Pyrazolopyridine inhibitors of B-RafV600E.Part 2:structure-activity relationships[J].Bioorg Med Chem Lett,2011,21(18):5 533-5 537.
[26]	Mathieu S,Gradl SN,Ren L,et al.Potent and selective aminopyrimidine-based B-Raf inhibitors with favorable physicochemical and pharmacokinetic properties[J].J Med Chem,2012,55(6):2 869-2 881.
[27]	Newhouse BJ,Wenglowsky S,Grina J,et al.Imidazo[4,5-b]pyridine inhibitors of B-Raf kinase[J].Bioorg Med Chem Lett,2013,23(21):5 896-5 899.
[28]	Ren L,Ahrendt KA,Grina J,et al.The discovery of potent and selective pyridopyrimidin-7-one based inhibitors of B-RafV600E kinase[J].Bioorg Med Chem Lett,2012,22(10):3 387-3 391.
[29]	Qin J,Xie P,Ventocilla C,et al.Identification of a novel family of BRAF(V600E)inhibitors[J].J Med Chem,2012,55(11):5 220-5 230.
[30]	Das Thakur M, Salangsang F, Landman AS, et al. Modelling vemurafenib resistance in melanoma reveals a strategy to forestall drug resistance[J].Nature,2013,494(7436):251-255.
[31]	Nijenhuis CM,Haanen JB,Schellens JH,et al.Is combination therapy the next step to overcome resistance and reduce toxicities in melanoma[J]?Cancer Treat Rev,2013,39(4):305-312.
[32]	Greger JG,Eastman SD,Zhang V,et al.Combinations of BRAF,MEK,and PI3K/mTOR inhibitors overcome acquired resistance to the BRAF inhibitor GSK2118436 dabrafenib,mediated by NRAS or MEK mutations[J].Mol Cancer Ther,2012,11(4):909-920.
[33]	Peters JU.Polypharmacology - foe or friend[J]?J Med Chem,2013,56(22):8 955-8 971.
[34]	Wenglowsky S,Moreno D,Laird ER,et al.Pyrazolopyridine inhibitors of B-Raf(V600E).Part 4:rational design and kinase selectivity profile of cell potent type II inhibitors[J].Bioorg Med Chem Lett,2012,22(19):6 237-6 241.

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