2011
DOI: 10.1016/j.bmcl.2011.01.062
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Design and synthesis of novel allosteric MEK inhibitor CH4987655 as an orally available anticancer agent

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Cited by 72 publications
(54 citation statements)
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“…CH5183284/Debio 1347 (FGFR inhibitor), CH4987655 (MEK inhibitor), CH5126766 (RAF-MEK inhibitor), and CH5132799 (PI3K inhibitor) were synthesized at Chugai Pharmaceutical Co. Ltd., as previously described (7,(16)(17)(18). AZD4547 was synthesized at Chugai Pharmaceutical Co. Ltd. (patent publication WO2008075068).…”
Section: Reagents and Cell Linesmentioning
confidence: 99%
“…CH5183284/Debio 1347 (FGFR inhibitor), CH4987655 (MEK inhibitor), CH5126766 (RAF-MEK inhibitor), and CH5132799 (PI3K inhibitor) were synthesized at Chugai Pharmaceutical Co. Ltd., as previously described (7,(16)(17)(18). AZD4547 was synthesized at Chugai Pharmaceutical Co. Ltd. (patent publication WO2008075068).…”
Section: Reagents and Cell Linesmentioning
confidence: 99%
“…On the basis of the data from a toxicity study in cynomolgus monkeys (15) and clinical data from healthy volunteers (16), a starting dose of 1.0 mg/day was chosen. A regimen of twice-daily dosing was also investigated, with a starting dose based on interim pharmacokinetics data from the once-daily regimen.…”
Section: Study Design and Dose Escalationmentioning
confidence: 99%
“…RO4987655 is a highly selective adenosine triphosphate noncompetitive oral MEK inhibitor that has shown promising antitumor activity in a series of human cancer xenograft models [non-small-cell lung cancer (NSCLC), pancreatic cancer, and hepatocellular carcinoma; ref. 15]. RO4987655 has a unique ring structure with a high metabolic stability and slow dissociation from MEK, which may confer better clinical efficacy compared with other MEK inhibitors (15).…”
Section: Introductionmentioning
confidence: 99%
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“…MEK 1/2 is the only enzyme known to activate ERK 1/2, ERK 1/2 being the only known substrate of MEK; therefore, MEK inhibition represents an attractive mechanism for blocking MAPK pathway activation (7). Recently, the MEK inhibitor trametinib has been shown to improve overall survival in BRAF V600-mutated metastatic melanoma (8) compared with dacarbazine or paclitaxel chemotherapy and has been approved by the Food and Drug Administration.…”
Section: Introductionmentioning
confidence: 99%