www.nature.com/aps
10
Wang GM et al
Discov Today 2009; 14: 291–7.
Li HF, Chen Y, Rao SS, Chen XM, Liu HC, Qin JH, et al. Recent advanc- 18 Zhang J, Yang PL, Gray NS. Targeting cancer with small molecule ki-
References
1
es in the research and development of B-Raf inhibitors. Curr Med
Chem 2010; 17: 1618–34.
Maik-Rachline G, Seger R. The ERK cascade inhibitors: towards over-
coming resistance. Drug Resist Updates 2016; 25: 1–12.
nase inhibitors. Nat Rev Cancer 2009; 9: 28–39.
19 Hoi PM, Li S, Vong CT, Tseng HH, Kwan YW, Lee SM. Recent advances
in structure-based drug design and virtual screening of VEGFR tyro-
sine kinase inhibitors. Methods 2015; 71: 85–91.
2
3
4
Uehling DE, Harris PA. Recent progress on MAP kinase pathway in- 20 Pemovska T, Johnson E, Kontro M, Repasky GA, Chen J, Wells P, et al.
hibitors. Bioorg Med Chem Lett 2015; 25: 4047–56.
Axitinib effectively inhibits BCR-ABL1(T315I) with a distinct binding
Menzies AM, Haydu LE, Visintin L, Carlino MS, Howle JR, Thompson JF,
conformation. Nature 2015; 519: 102–5.
et al. Distinguishing clinicopathologic features of patients with V600E 21 Kumar A, Voet A, Zhang KY. Fragment based drug design: from ex-
and V600K BRAF-mutant metastatic melanoma. Clin Cancer Res
012; 18: 3242–9.
perimental to computational approaches. Curr Med Chem 2012; 19:
5128–47.
2
5
Cancer Genome Atlas Research Network. Integrated genomic charac- 22 Roberts AW, Davids MS, Pagel JM, Kahl BS, Puvvada SD, Gerecitano
terization of papillary thyroid carcinoma. Cell 2014; 159: 676–90.
JF, et al. Targeting BCL2 with venetoclax in relapsed chronic lympho-
6
Yokota T, Ura T, Shibata N, Takahari D, Shitara K, Nomura M, et al.
cytic leukemia. N Engl J Med 2016; 374: 311–22.
BRAF mutation is a powerful prognostic factor in advanced and recur- 23 Joseph-McCarthy D, Campbell AJ, Kern G, Moustakas D. Fragment-
rent colorectal cancer. Br J Cancer 2011; 104: 856–62.
based lead discovery and design. J Chem Inf Model 2014; 54: 693–
7
8
9
Fransen K, Klintenas M, Osterstrom A, Dimberg J, Monstein HJ,
704.
Soderkvist P. Mutation analysis of the BRAF, ARAF and RAF-1 genes 24 Radoux CJ, Olsson TS, Pitt WR, Groom CR, Blundell TL. Identifying
in human colorectal adenocarcinomas. Carcinogenesis 2004; 25:
27–33.
interactions that determine fragment binding at protein hotspots. J
Med Chem 2016; 59: 4314–25.
DeFazio A, Moujaber T, Etemadmoghadam D, Kennedy C, Chiew YE, 25 Pipeline Pilot; Accelrys Software Inc: San Diego, CA, USA.
mutations in serous ovar- 26 LigPrep, version 2.4, Schrödinger, LLC: New York, NY, USA, 2010.
ian cancer and response to the BRAF inhibitor, dabrafenib. Clin Can- 27 Epik, version 2.1; Schro dinger, LLC: New York, NY, USA, 2010.
5
V600E
Balleine RL, et al. Abstract A25: BRAF
cer Res 2016; 22: A25.
28 Shelley JC, Cholleti A, Frye LL, Greenwood JR, Timlin MR, Uchimaya
Brastianos PK, Taylor-Weiner A, Manley PE, Jones RT, Dias-Santagata
D, Thorner AR, et al. Exome sequencing identifies BRAF mutations in
papillary craniopharyngiomas. Nat Genet 2014; 46: 161–5.
M. Epik: a software program for pK prediction and protonation state
generation for drug-like molecules. J Comput Aided Mol Des 2007;
21: 681–91.
a
1
0 Fiskus W, Mitsiades N. B-Raf inhibition in the clinic: present and 29 Friesner RA, Banks JL, Murphy RB, Halgren TA, Klicic JJ, Mainz DT, et
future. Annu Rev Med 2016; 67: 29–43.
al. Glide: a new approach for rapid, accurate docking and scoring. 1.
Method and assessment of docking accuracy. J Med Chem 2004; 47:
1739–49.
1
1 Qin J, Xie P, Ventocilla C, Zhou G, Vultur A, Chen Q, et al. Identifica-
V600E
tion of a novel family of BRAF
220–30.
inhibitors. J Med Chem 2012; 55:
5
30 Halgren TA, Murphy RB, Friesner RA, Beard HS, Frye LL, Pollard WT,
et al. Glide: a new approach for rapid, accurate docking and scoring.
2. Enrichment factors in database screening. J Med Chem 2004; 47:
1750–9.
31 Friesner RA, Murphy RB, Repasky MP, Frye LL, Greenwood JR, Halgren
TA, et al. Extra precision glide: docking and scoring incorporating a
model of hydrophobic enclosure for protein-ligand complexes. J Med
Chem 2006; 49: 6177–96.
1
2 Xu Z, Yan G, Wang G, Li B, Zhu J, Sun P, et al. Combining pharmaco-
phore, docking and substructure search approaches to identify and
V600E
optimize novel B-Raf
428–37.
inhibitors. Bioorg Med Chem Lett 2012; 22:
5
1
3 Bollag G, Hirth P, Tsai J, Zhang J, Ibrahim PN, Cho H, et al. Clinical ef-
ficacy of a RAF inhibitor needs broad target blockade in BRAF-mutant
melanoma. Nature 2010; 467: 596–9.
1
4 Flaherty KT, Yasothan U, Kirkpatrick P. Vemurafenib. Nat Rev Drug 32 Tolosa L, Donato MT, Gomez-Lechon MJ. General cytotoxicity assess-
Discov 2011; 10: 811–2.
ment by means of the MTT assay. Methods Mol Biol 2015; 1250:
15 Zhang C, Spevak W, Zhang Y, Burton EA, Ma Y, Habets G, et al. RAF
333–48.
inhibitors that evade paradoxical MAPK pathway activation. Nature 33 Xie P, Streu C, Qin J, Bregman H, Pagano N, Meggers E, et al. The
2
015; 526: 583–6.
6 Sun XX, Yu Q. Intra-tumor heterogeneity of cancer cells and its impli-
cations for cancer treatment. Acta Pharmacol Sin 2015; 36: 1219–
7.
7 Akritopoulou-Zanze I, Hajduk PJ. Kinase-targeted libraries: the design
and synthesis of novel, potent, and selective kinase inhibitors. Drug
crystal structure of BRAF in complex with an organoruthenium
inhibitor reveals a mechanism for inhibition of an active form of BRAF
kinase. Biochemistry 2009; 48: 5187–98.
1
2
34 Tsai J, Lee JT, Wang W, Zhang J, Cho H, Mamo S, et al. Discovery
of a selective inhibitor of oncogenic B-Raf kinase with potent anti-
melanoma activity. Proc Natl Acad Sci U S A 2008; 105: 3041–6.
1
Acta Pharmacologica Sinica