title: Identification and optimization of new dual inhibitors of B-Raf and epidermal growth factor receptor kinases for overcoming resistance against vemurafenib.
abstract: Epidermal growth factor receptor (EGFR) amplification has been demonstrated to be critical for the inherent and/or acquired resistance against current B-Raf(V600E) inhibitor therapy for melanoma and colorectal cancer patients. We describe the discovery and structure-activity relationship study of a series of 1H-pyrazolo[3,4-b]pyridine-5-carboxamide analogues as novel dual inhibitors of EGFR and B-Raf(V600E) mutant. One of the most promising compounds, 6a, potently inhibited both of the kinases with IC50 values of 8.0 and 51 nM, respectively. The compound also strongly suppressed the proliferation of a panel of intrinsic and acquired resistant melanoma and/or colorectal cancer cells harboring overexpressed EGFR with submicromolar IC50 values. Further mechanism investigation revealed that 6a could sustainably inhibit the activation of the MAPK path way in the resistant SK-MEL-28 PR30 melanoma cancer cells and WiDr colorectal cancer cells with EGFR amplification. Our results support the hypothesis that the EGFR/B-Raf(V600E) dual inhibition might be a tractable strategy to overcome the intrinsic and acquired resistance of melanoma and/or colorectal cancers against the current B-Raf(V600E) inhibitor therapy.
authors.affiliation: Institute of Chemical Biology, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences , #190 Kaiyuan Avenue, Guangzhou 510530, China.
authors.forename: Huimin
authors.initials: H
authors.lastname: Cheng
authors.forename: Yu
authors.initials: Y
authors.lastname: Chang
authors.forename: Lianwen
authors.initials: L
authors.lastname: Zhang
authors.forename: Jinfeng
authors.initials: J
authors.lastname: Luo
authors.forename: Zhengchao
authors.initials: Z
authors.lastname: Tu
authors.forename: Xiaoyun
authors.initials: X
authors.lastname: Lu
authors.forename: Qingwen
authors.initials: Q
authors.lastname: Zhang
authors.forename: Jibu
authors.initials: J
authors.lastname: Lu
authors.forename: Xiaomei
authors.initials: X
authors.lastname: Ren
authors.forename: Ke
authors.initials: K
authors.lastname: Ding
mesh_terms: D015153:Blotting, Western; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D015179:Colorectal Neoplasms / Q000188:drug therapy; D004353:Drug Evaluation, Preclinical; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D066246:ErbB Receptors / Q000187:drug effects* / Q000235:genetics; D018773:Genes, erbB-1 / Q000187:drug effects / Q000235:genetics; D006801:Humans; D007202:Indicators and Reagents; D007211:Indoles / Q000494:pharmacology*; D008545:Melanoma / Q000188:drug therapy; D020928:Mitogen-Activated Protein Kinases / Q000187:drug effects / Q000502:physiology; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology; D048493:Proto-Oncogene Proteins B-raf / Q000187:drug effects* / Q000235:genetics; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000494:pharmacology*; D000077484:Vemurafenib
chemical_list: D007202:Indicators and Reagents; D007211:Indoles; D047428:Protein Kinase Inhibitors; D013449:Sulfonamides; D000077484:Vemurafenib; D066246:ErbB Receptors; D048493:Proto-Oncogene Proteins B-raf; D020928:Mitogen-Activated Protein Kinases