GSK1120212 (JTP-74057) Is an Inhibitor of MEK Activity and Activation with Favorable Pharmacokinetic Properties for Sustained In Vivo Pathway Inhibition

Abstract

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's enzymatic, cellular, and in vivo activities, describing its unusually long circulating half-life.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.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 p27Kip1/CDKN1B , and caused tumor growth inhibition in multiple tumor models. The largest antitumor effect was among tumors harboring mutant BRAF or Ras. 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.

Increased MAPK reactivation in early resistance to dabrafenib/trametinib combination therapy of BRAF-mutant metastatic melanoma

“…Although trametinib shows similar inhibitory activity towards the MEK1 and MEK2 proteins in in vitro ERK kinase assays 36 , we observed a preponderance of MEK2 mutations rather than MEK1 mutations in CombiDT-resistant Progs. The fact that the MEK2 C125S mutation and not the homologous MEK1 C121S conferred robust resistance to combination therapy in our preclinical models highlights the functional differences between these highly homologous kinases.…”

Rapid Renal Regulation of Peroxisome Proliferator-activated Receptor γ Coactivator-1α by Extracellular Signal-Regulated Kinase 1/2 in Physiological and Pathological Conditions

“…Trametinib has been well characterized as a potent and specific inhibitor of MEK1/2 with an IC 50 of 0.92-3.4 nM in various cell lines and shows limited inhibitory activity against at least 98 other kinases (15,16). RPTC were treated with 0.3, 1, or 10 nM trametinib, and at 10 nM trametinib, ERK1/2 phosphorylation was completely inhibited after 4 h (Fig.…”

Pten loss promotes MAPK pathway dependency in HER2/neu breast carcinomas

“…5). In all, we assessed four treatment arms using agents targeting oncogenic HER2/neu (Lapatinib), PI3K/Akt signaling (α-Akt: MK-2206; α-pan-PI3K: NVP-BKM120), or Mek/Erk activity (α-Mek: GSK1120212) at doses routinely used in preclinical studies (15,29,31,32). Drug efficacy against the mouse protein target was verified by assessing the impact on signaling in treated tumor protein extracts (Fig.…”