title: Discovery of highly selective CRAF inhibitors, 3-carboxamido-2H-indazole-6-arylamide: In silico FBLD design, synthesis and evaluation.
abstract: The recent success of vemurafenib shows the importance of selective BRAF V600E inhibition in melanoma. However, paradoxical activation by structurally diverse ATP-competitive RAF kinase inhibitors strongly suggests that selective CRAF inhibitors, not BRAF inhibitors, would be ideal for some Ras mutation cancer treatment. In this respect, we approached designing selective CRAF inhibitors starting from in silico fragment screening and synthesized a 3-carboxamido-2H-indazole-6-arylamide scaffold. Most of the compounds showed potent antiproliferative activity against the WM3629 melanoma cell line and the most promising compound, compound 10d, was found to be a potent and selective CRAF inhibitor with an IC50 value of 38.6 nM, which shows greater than 270-fold selectivity over BRAF kinase (9.45 μM).
authors.affiliation: Department of Pharmacy, College of Pharmacy & Institute of Pharmaceutical Science and Technology, Hanyang University, 55 Hanyangdaehak-ro, Sangnok-gu, Ansan, Kyeonggi-do 426-791, Republic of Korea.
authors.forename: Waqar
authors.initials: W
authors.lastname: Aman
authors.affiliation: Department of Pharmacy, College of Pharmacy & Institute of Pharmaceutical Science and Technology, Hanyang University, 55 Hanyangdaehak-ro, Sangnok-gu, Ansan, Kyeonggi-do 426-791, Republic of Korea.
authors.forename: Junghun
authors.initials: J
authors.lastname: Lee
authors.affiliation: Department of Pharmacy, College of Pharmacy & Institute of Pharmaceutical Science and Technology, Hanyang University, 55 Hanyangdaehak-ro, Sangnok-gu, Ansan, Kyeonggi-do 426-791, Republic of Korea.
authors.forename: Minjung
authors.initials: M
authors.lastname: Kim
authors.affiliation: Department of Pharmacy, College of Pharmacy & Institute of Pharmaceutical Science and Technology, Hanyang University, 55 Hanyangdaehak-ro, Sangnok-gu, Ansan, Kyeonggi-do 426-791, Republic of Korea.
authors.forename: Songyi
authors.initials: S
authors.lastname: Yang
authors.affiliation: Department of Pharmacy, College of Pharmacy & Institute of Pharmaceutical Science and Technology, Hanyang University, 55 Hanyangdaehak-ro, Sangnok-gu, Ansan, Kyeonggi-do 426-791, Republic of Korea.
authors.forename: Hoyong
authors.initials: H
authors.lastname: Jung
authors.affiliation: Department of Pharmacy, College of Pharmacy & Institute of Pharmaceutical Science and Technology, Hanyang University, 55 Hanyangdaehak-ro, Sangnok-gu, Ansan, Kyeonggi-do 426-791, Republic of Korea. Electronic address: jhah@hanyang.ac.kr.
authors.forename: Jung-Mi
authors.initials: JM
authors.lastname: Hah
mesh_terms: D000577:Amides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D001665:Binding Sites; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D015195:Drug Design; D006801:Humans; D007191:Indazoles / Q000737:chemistry*; D062105:Molecular Docking Simulation; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000633:toxicity; D017434:Protein Structure, Tertiary; D019908:Proto-Oncogene Proteins c-raf / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D000577:Amides; D007191:Indazoles; D047428:Protein Kinase Inhibitors; D019908:Proto-Oncogene Proteins c-raf
keywords: BRAF V600E; CRAF; Melanoma; Selectivity