Abstract
Melanomas represent only 4% of all skin cancers, but their mortality rate is more than 50 % of any other
skin cancer. Alteration in genetic and environmental factors are the risk factors for melanoma development. The
RAS/RAF/MEK/ERK or Mitogen-activated protein kinase (MAPK) pathway is activated in melanoma. BRAF activation
is necessary to govern differentiation, proliferation, and survival. Mutations in BRAF were found in 80–90% of all
melanomas. Over 90% of BRAF mutations occur at codon 600, and over 90% of them are BRAFV600E other common
mutations are BRAFV600K, BRAFV600R, BRAF V600′E2′, and BRAF V600D. Based on αC-helix and DFG motif
(αC-helix-IN/DFG-IN), (αC-helix-IN/DFG-OUT), (αC-helix-OUT/DFG-IN) and (αC-helix-OUT/ DFG-OUT) are four
structural types of inhibitors for targeting BRAF. Sorafenib, Vemurafenib, Dabrafenib, and Encorafenib are FDAapproved
for the treatment of BRAF. Understanding melanoma pathogenesis, RAS/RAF/MEK/ERK or MAPK pathway,
and BRAF conformations, mutations, the problems with FDA approved BRAF inhibitors will be important for
new drug discovery, modification of existing BRAF barriers to improve target specific action, and prevent increasing
response levels while minimizing toxicity.
Keywords:
Melanoma, RAS, RAF, MAPK, BRAF, αC-helix, DFG motif.
Graphical Abstract
[2]
Arrangoiz, R.; Dorantes, J.; Cordera, F.; Juarez, M.M.; Paquentin, E.M. Melanoma review: Epidemiology, risk factors, diagnosis, and staging. J. Cancer Res. Pract., 2016, 4(1), 1-15.
[7]
Linares, M.A.; Zakaria, A.; Nizran, P. Skin cancer. Prim. Care - Clin. Off. Pract., 2015, 42(4), 645-659.
[18]
Palmieri, G.; Rozzo, C.; Gentilcore, G.; Ascierto, P.A. Melanoma pathophysiology and drug targets. In: Future Medicine; , 2012; pp. 6-17.
[23]
Zito, P.M.; Scharf, R. Melanoma of the head and neck; StatPearls: Treasure Island, 2021.
[37]
Matthews, N.H.; Li, W-Q.; Qureshi, A.A.; Weinstock, M.A.; Cho, E. Epidemiology of melanoma In: Cutaneous Melanoma Codon Publ., Singapore; , 2017; pp. 3-22.
[38]
Kyrgidis, A. Melanoma epidemiology. In: Cutaneous Melanoma; Elsevier: Amsterdam, 2017; pp. 1-9.
[50]
Figel, S.; Fenstermaker, R.A. Cell-cycle regulation. In: Handbook of Brain Tumor Chemotherapy, Molecular Therapeutics, and Immuno-therapy; Elsevier: Amsterdam, 2018; pp. 257-269.
[72]
Palmieri, G.; Colombino, M.; Sini, M.C.; Ascierto, P.A.; Lissia, A.; Cossu, A. Targeted therapies in melanoma: Successes and pitfalls. In: Melanoma-From Early Detection to Treatment; , 2013; pp. 29-58.
[154]
Vargas-Ibarra, D.; Velez-Vasquez, M.; Bermudez-Munoz, M. Regulation of MAPK ERK1/2 signaling by phosphorylation: Implications in physiological and pathological contexts. In: Post-Translational Modifications in Cellular Functions and Diseases; IntechOpen, 2021.
[160]
Friedman, J.A.; Hewit, T.; Bruckheimer, E.; Trusko, S.; Dorsey, B.; Ruggeri, B. Antitumor activity of CEP-32496, a novel orally active BRAFV600E inhibitor, in a panel of champions tumor graft models of melanoma and colorectal cancer with B-Raf V600E mutations. AACR, 2012, 72(8), 3755-3755.
[177]
Nishiguchi, G.A.; Rico, A.; Tanner, H.; Aversa, R.J.; Taft, B.R.; Subramanian, S.; Setti, L.; Burger, M.T.; Wan, L.; Tamez, V.; Smith, A.; Lou, Y.; Barsanti, P.A.; Appleton, B.A.; Mamo, M.; Tandeske, L.; Dix, I.; Tellew, J.E.; Huang, S.; Mathews Griner, L.A.; Cooke, V.G.; Van Abbema, A.; Merritt, H.; Ma, S.; Gampa, K.; Feng, F.; Yuan, J.; Wang, Y.; Haling, J.R.; Vaziri, S.; Hekmat-Nejad, M.; Jansen, J.M.; Polyakov, V.; Zang, R.; Sethuraman, V.; Amiri, P.; Singh, M.; Lees, E.; Shao, W.; Stuart, D.D.; Dillon, M.P.; Ramurthy, S. Design and Discovery of N-(2-Methyl-5′-morpholino-6′-((tetrahydro-2H-pyran-4-yl)oxy)-[3,3′-bipyridin]-5-yl)-3-(trifluoromethyl)benzamide (RAF709): A potent, selective, and efficacious RAF inhibitor targeting RAS mutant cancers.
J. Med. Chem., 2017,
60(12), 4869-4881.
[
http://dx.doi.org/10.1021/acs.jmedchem.6b01862] [PMID:
28557458]
Download PDF Flyer