| Reference | 1. Clin Cancer Res. 2011 Mar 1;17(5):989-1000. doi: 10.1158/1078-0432.CCR-10-2200.
Epub 2011 Jan 18. <br />
GSK1120212 (JTP-74057) is an inhibitor of MEK activity and activation with
favorable pharmacokinetic properties for sustained in vivo pathway inhibition. <br />
Gilmartin AG(1), Bleam MR, Groy A, Moss KG, Minthorn EA, Kulkarni SG, Rominger
CM, Erskine S, Fisher KE, Yang J, Zappacosta F, Annan R, Sutton D, Laquerre SG. <br />
Author information: <br />
(1)GlaxoSmithKline, Collegeville, Pennsylvania 19426, USA.
[email protected] <br />
Erratum in<br />
Clin Cancer Res. 2012 Apr 15;18(8):2413. <br />
PURPOSE: Despite their preclinical promise, previous MEK inhibitors have shown
little benefit for patients. This likely reflects the narrow therapeutic window
for MEK inhibitors due to the essential role of the P42/44 MAPK pathway in many
nontumor tissues. GSK1120212 is a potent and selective allosteric inhibitor of
the MEK1 and MEK2 (MEK1/2) enzymes with promising antitumor activity in a phase I
clinical trial (ASCO 2010). Our studies characterize GSK1120212/’ enzymatic,
cellular, and in vivo activities, describing its unusually long circulating
half-life.<br />
EXPERIMENTAL DESIGN: Enzymatic studies were conducted to determine GSK1120212
inhibition of recombinant MEK, following or preceding RAF kinase activation.
Cellular studies examined GSK1120212 inhibition of ERK1 and 2 phosphorylation
(p-ERK1/2) as well as MEK1/2 phosphorylation and activation. Further studies
explored the sensitivity of cancer cell lines, and drug pharmacokinetics and
efficacy in multiple tumor xenograft models.<br />
RESULTS: In enzymatic and cellular studies, GSK1120212 inhibits MEK1/2 kinase
activity and prevents Raf-dependent MEK phosphorylation (S217 for MEK1),
producing prolonged p-ERK1/2 inhibition. Potent cell growth inhibition was
evident in most tumor lines with mutant BRAF or Ras. In xenografted tumor models,
GSK1120212 orally dosed once daily had a long circulating half-life and sustained
suppression of p-ERK1/2 for more than 24 hours; GSK1120212 also reduced tumor
Ki67, increased p27(Kip1/CDKN1B), and caused tumor growth inhibition in multiple
tumor models. The largest antitumor effect was among tumors harboring mutant BRAF
or Ras.<br />
CONCLUSIONS: GSK1120212 combines high potency, selectivity, and long circulating
half-life, offering promise for successfully targeting the narrow therapeutic
window anticipated for clinical MEK inhibitors. <br />
2. ACS Med Chem Lett. 2011 Feb 28;2(4):320-4. doi: 10.1021/ml200004g. eCollection
2011 Apr 14. <br />
Discovery of a Highly Potent and Selective MEK Inhibitor: GSK1120212 (JTP-74057
DMSO Solvate). <br />
Abe H(1), Kikuchi S(1), Hayakawa K(1), Iida T(1), Nagahashi N(1), Maeda K(1),
Sakamoto J(1), Matsumoto N(1), Miura T(1), Matsumura K(1), Seki N(1), Inaba T(1),
Kawasaki H(1), Yamaguchi T(1), Kakefuda R(1), Nanayama T(1), Kurachi H(1), Hori
Y(1), Yoshida T(2), Kakegawa J(2), Watanabe Y(2), Gilmartin AG(3), Richter MC(3),
Moss KG(3), Laquerre SG(3). <br />
Author information: <br />
(1)Central Pharmaceutical Research Institute, Japan Tobacco, 1-1 Murasaki-cho,
Takatsuki, Osaka 569-1125, Japan.
(2)Pharmaceutical Frontier Research Laboratory, Japan Tobacco, 1-13-2 Fukuura,
Kanazawa-ku, Yokohama, Kanagawa 236-0004, Japan.
(3)Oncology R&D, GlaxoSmithKline, 1250 South Collegeville Road, Collegeville,
Pennsylvania 19426, United States. <br />
Inhibition of mitogen-activated protein kinase/extracellular signal-regulated
kinase kinase (MEK) represents a promising strategy for the discovery of a new
generation of anticancer chemotherapeutics. Our synthetic efforts, beginning from
the lead compound 2, were directed at improving antiproliferative activity
against cancer cells as well as various drug properties. These efforts led to the
discovery of
N-{3-[3-cyclopropyl-5-(2-fluoro-4-iodophenylamino)-6,8-dimethyl-2,4,7-trioxo-3,4,
6,7-tetrahydro-2H-pyrido[4,3-d]pyrimidin-1-yl]phenyl}acetamide dimethylsulfoxide
solvate (GSK1120212, JTP-74057 DMSO solvate; 1), a selective and highly potent
MEK inhibitor with improved drug properties. We further confirmed that the
antiproliferative activity correlates with cellular MEK inhibition and observed
significant antitumor activity with daily oral dosing of 1 in a tumor xenograft
model. These qualities led to the selection of 1 for clinical development. <br />
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