title: Enhanced inhibition of ERK signaling by a novel allosteric MEK inhibitor, CH5126766, that suppresses feedback reactivation of RAF activity.
abstract: Tumors with mutant RAS are often dependent on extracellular signal-regulated kinase (ERK) signaling for growth; however, MEK inhibitors have only marginal antitumor activity in these tumors. MEK inhibitors relieve ERK-dependent feedback inhibition of RAF and cause induction of MEK phosphorylation. We have now identified a MEK inhibitor, CH5126766 (RO5126766), that has the unique property of inhibiting RAF kinase as well. CH5126766 binding causes MEK to adopt a conformation in which it cannot be phosphorylated by and released from RAF. This results in formation of a stable MEK/RAF complex and inhibition of RAF kinase. Consistent with this mechanism, this drug does not induce MEK phosphorylation. CH5126766 inhibits ERK signaling output more effectively than a standard MEK inhibitor that induces MEK phosphorylation and has potent antitumor activity as well. These results suggest that relief of RAF feedback limits pathway inhibition by standard MEK inhibitors. CH5126766 represents a new type of MEK inhibitor that causes MEK to become a dominant-negative inhibitor of RAF and that, in doing so, may have enhanced therapeutic activity in ERK-dependent tumors with mutant RAS.
authors.affiliation: Kamakura Research Laboratory, Research Division, Chugai Pharmaceutical Co., Ltd., Kamakura, Japan.
authors.forename: Nobuya
authors.initials: N
authors.lastname: Ishii
authors.affiliation: Kamakura Research Laboratory, Research Division, Chugai Pharmaceutical Co., Ltd., Kamakura, Japan.
authors.forename: Naoki
authors.initials: N
authors.lastname: Harada
authors.affiliation: Program in Molecular Pharmacology and Chemistry, Memorial Sloan-Kettering Cancer Center, New York.
authors.forename: Eric W
authors.initials: EW
authors.lastname: Joseph
authors.affiliation: Kamakura Research Laboratory, Research Division, Chugai Pharmaceutical Co., Ltd., Kamakura, Japan.
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Ohara
authors.affiliation: Kamakura Research Laboratory, Research Division, Chugai Pharmaceutical Co., Ltd., Kamakura, Japan.
authors.forename: Takaaki
authors.initials: T
authors.lastname: Miura
authors.affiliation: Kamakura Research Laboratory, Research Division, Chugai Pharmaceutical Co., Ltd., Kamakura, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Sakamoto
authors.affiliation: Kamakura Research Laboratory, Research Division, Chugai Pharmaceutical Co., Ltd., Kamakura, Japan.
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Matsuda
authors.affiliation: Kamakura Research Laboratory, Research Division, Chugai Pharmaceutical Co., Ltd., Kamakura, Japan.
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Tomii
authors.affiliation: Kamakura Research Laboratory, Research Division, Chugai Pharmaceutical Co., Ltd., Kamakura, Japan.
authors.forename: Yukako
authors.initials: Y
authors.lastname: Tachibana-Kondo
authors.affiliation: Kamakura Research Laboratory, Research Division, Chugai Pharmaceutical Co., Ltd., Kamakura, Japan.
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Iikura
authors.affiliation: Kamakura Research Laboratory, Research Division, Chugai Pharmaceutical Co., Ltd., Kamakura, Japan.
authors.forename: Toshihiro
authors.initials: T
authors.lastname: Aoki
authors.affiliation: Kamakura Research Laboratory, Research Division, Chugai Pharmaceutical Co., Ltd., Kamakura, Japan.
authors.forename: Nobuo
authors.initials: N
authors.lastname: Shimma
authors.affiliation: Kamakura Research Laboratory, Research Division, Chugai Pharmaceutical Co., Ltd., Kamakura, Japan.
authors.forename: Mikio
authors.initials: M
authors.lastname: Arisawa
authors.affiliation: Department of Molecular-Targeting Cancer Prevention, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan.
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Sowa
authors.affiliation: Program in Molecular Pharmacology and Chemistry, Memorial Sloan-Kettering Cancer Center, New York.
authors.forename: Poulikos I
authors.initials: PI
authors.lastname: Poulikakos
authors.affiliation: Program in Molecular Pharmacology and Chemistry, Memorial Sloan-Kettering Cancer Center, New York.
authors.forename: Neal
authors.initials: N
authors.lastname: Rosen
authors.affiliation: Kamakura Research Laboratory, Research Division, Chugai Pharmaceutical Co., Ltd., Kamakura, Japan.
authors.forename: Yuko
authors.initials: Y
authors.lastname: Aoki
authors.affiliation: Department of Molecular-Targeting Cancer Prevention, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan.
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Sakai
mesh_terms: D000494:Allosteric Regulation; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D003374:Coumarins / Q000494:pharmacology*; D004789:Enzyme Activation / Q000187:drug effects; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D025461:Feedback, Physiological / Q000187:drug effects; D005260:Female; D006801:Humans; D048369:MAP Kinase Kinase 1 / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D010766:Phosphorylation; D011485:Protein Binding; D011499:Protein Processing, Post-Translational; D011518:Proto-Oncogene Proteins / Q000235:genetics; D048493:Proto-Oncogene Proteins B-raf / Q000737:chemistry / Q000378:metabolism*; D019908:Proto-Oncogene Proteins c-raf / Q000737:chemistry / Q000378:metabolism; D016283:Proto-Oncogene Proteins p21(ras); D023041:Xenograft Model Antitumor Assays; D018631:ras Proteins / Q000235:genetics
chemical_list: D000970:Antineoplastic Agents; D003374:Coumarins; C117307:KRAS protein, human; D011518:Proto-Oncogene Proteins; C577924:RO5126766; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D019908:Proto-Oncogene Proteins c-raf; D048049:Extracellular Signal-Regulated MAP Kinases; D048369:MAP Kinase Kinase 1; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins