Identification of JTP‐70902, a p15<sup>INK4b</sup>‐inductive compound, as a novel MEK1/2 inhibitor

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.

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“…13,14). GSK1120212 is a DMSO solvate compound (ratio 1:1) with potent and ATP noncompetitive inhibition of MEK1/2 ( Supplementary Fig.…”

Section: Resultsmentioning

confidence: 99%

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

Gilmartin

Bleam

Groy

et al. 2011

Clinical Cancer Research

541

483

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“…1,2,6 During a high-throughput screening for compounds that can induce expression of the cyclin-dependent kinase (CDK) 4/6 inhibitor p15 INK4b , we identified 2 ( Figure 1). 7 Subsequent experiments confirmed that 2 has an antiproliferative activity against human cancer cell lines ACHN (renal adenocarcinoma) and HT-29 (colorectal adenocarcinoma) with IC 50 values of 4800 and 990 nM, respectively. We conducted a medicinal chemistry campaign, chemically modifying 2 to optimize for these antiproliferative effects.…”

mentioning

confidence: 89%

“…As a result, we found that 8b binds to MEK1/2 and inhibits its kinase activity with high specificity. 7,8,10,11 To confirm that cellular antiproliferative activity is due to cellular inhibition of MEK1/2 kinase activity, the DMSO solvate 1 was tested in both a cellular phospho-ERK1/2 assay and cell proliferation assays. In BRAF mutant SK-MEL-28 cells and KRAS mutant HCT116 cells, 1 caused dose-dependent inhibition of ERK1/2 phosphorylation as well as dose-dependent growth inhibition.…”

mentioning

confidence: 99%

Discovery of a Highly Potent and Selective MEK Inhibitor: GSK1120212 (JTP-74057 DMSO Solvate)

Abé

Kikuchi

Hayakawa

et al. 2011

ACS Med. Chem. Lett.

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144

119

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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.

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“…Key toxicities include hyperglycemia, neuropsychiatric disorders, liver toxicity, skin rash and hypersensitivity, and gastrointestinal toxicity. Trametinib (GSK1120212; Mekinist) is a reversible, highly selective allosteric inhibitor of MEK1/MEK2 activation and kinase activity (11,12). MTD and RP2D of trametinib are 3 and 2 mg/d, respectively (13,14).…”

Section: Introductionmentioning

confidence: 99%

A Phase Ib Dose-Escalation Study of the Oral Pan-PI3K Inhibitor Buparlisib (BKM120) in Combination with the Oral MEK1/2 Inhibitor Trametinib (GSK1120212) in Patients with Selected Advanced Solid Tumors

Bedard

Tabernero

Janků

et al. 2015

Clinical Cancer Research

283

176

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Purpose: MAPK and PI3K/AKT/mTOR pathways play important roles in many tumors. In this study, safety, antitumor activity, and pharmacokinetics of buparlisib (pan class PI3K inhibitor) and trametinib (MEK inhibitor) were evaluated.Experimental Design: This open-label, dose-finding, phase Ib study comprised dose escalation, followed by expansion part in patients with RAS-or BRAF-mutant non-small cell lung, ovarian, or pancreatic cancer.Results: Of note, 113 patients were enrolled, 66 and 47 in doseescalation and -expansion parts, respectively. MTD was established as buparlisib 70 mg þ trametinib 1.5 mg daily [5/15, 33% patients with dose-limiting toxicities (DLT)] and recommended phase II dose (RP2D) buparlisib 60 mg þ trametinib 1.5 mg daily (1/10, 10% patients with DLTs). DLTs included stomatitis (8/103, 8%), diarrhea, dysphagia, and creatine kinase (CK) increase (2/103, 2% each). Treatment-related grade 3/4 adverse events (AEs) occurred in 73 patients (65%); mainly CK increase, stomatitis, AST/ALT (aspartate aminotransferase/alanine aminotransferase) increase, and rash. For all (21) patients with ovarian cancer, overall response rate was 29% [1 complete response, 5 partial responses (PR)], disease control rate 76%, and median progression-free survival was 7 months. Minimal activity was observed in patients with non-small cell lung cancer (1/17 PR) and pancreatic cancer (best overall response was SD). Relative to historical data, buparlisib exposure increased and trametinib exposure slightly increased with the combination.Conclusions: At RP2D, buparlisib 60 mg þ trametinib 1.5 mg daily shows promising antitumor activity for patients with KRAS-mutant ovarian cancer. Long-term tolerability of the combination at RP2D is challenging, due to frequent dose interruptions and reductions for toxicity.

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Identification of JTP‐70902, a p15^INK4b‐inductive compound, as a novel MEK1/2 inhibitor

Cited by 50 publications

References 43 publications

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

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

Discovery of a Highly Potent and Selective MEK Inhibitor: GSK1120212 (JTP-74057 DMSO Solvate)

A Phase Ib Dose-Escalation Study of the Oral Pan-PI3K Inhibitor Buparlisib (BKM120) in Combination with the Oral MEK1/2 Inhibitor Trametinib (GSK1120212) in Patients with Selected Advanced Solid Tumors

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Identification of JTP‐70902, a p15INK4b‐inductive compound, as a novel MEK1/2 inhibitor

Cited by 50 publications

References 43 publications

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

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

Discovery of a Highly Potent and Selective MEK Inhibitor: GSK1120212 (JTP-74057 DMSO Solvate)

A Phase Ib Dose-Escalation Study of the Oral Pan-PI3K Inhibitor Buparlisib (BKM120) in Combination with the Oral MEK1/2 Inhibitor Trametinib (GSK1120212) in Patients with Selected Advanced Solid Tumors

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Identification of JTP‐70902, a p15^INK4b‐inductive compound, as a novel MEK1/2 inhibitor