The discovery of the benzhydroxamate MEK inhibitors CI-1040 and PD 0325901

Barrett, Stephen D.; Bridges, Alexander J.; Dudley, David T.; Saltiel, Alan R.; Fergus, James H.; Flamme, Cathlin; Delaney, Amy M.; Kaufman, Michael D.; Lepage, Sophie; Leopold, Wilbur R.; Przybranowski, Sally; Sebolt–Leopold, Judith S.; Becelaere, Keri Van; Doherty, Annette M.; Kennedy, Robert M.; Marston, Dan; Howard, W. Allen; Smith, Yvonne; Warmus, Joseph S.; Tecle, Haile

doi:10.1016/j.bmcl.2008.10.054

Cited by 259 publications

(204 citation statements)

References 17 publications

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“…PLX4032 was obtained from Plexxikon, Inc. PD0325901 was synthesized according to its published structure (35). Drugs for in vitro studies were dissolved in DMSO stock solutions and stored at −20°C.…”

Section: Methodsmentioning

confidence: 99%

The RAF inhibitor PLX4032 inhibits ERK signaling and tumor cell proliferation in a V600E BRAF-selective manner

Joseph

Pratilas

Poulikakos³

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

423

352

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Tumors with mutant BRAF and some with mutant RAS are dependent upon ERK signaling for proliferation, and their growth is suppressed by MAPK/ERK kinase (MEK) inhibitors. In contrast, tumor cells with human EGF receptor (HER) kinase activation proliferate in a MEK-independent manner. These findings have led to the development of RAF and MEK inhibitors as anticancer agents. Like MEK inhibitors, the RAF inhibitor PLX4032 inhibits the proliferation of BRAF V600E tumor cells but not that of HER kinase-dependent tumors. However, tumors with RAS mutation that are sensitive to MEK inhibition are insensitive to PLX4032. MEK inhibitors inhibit ERK phosphorylation in all normal and tumor cells, whereas PLX4032 inhibits ERK signaling only in tumor cells expressing BRAF V600E . In contrast, the drug activates MEK and ERK phosphorylation in cells with wildtype BRAF. In BRAF V600E tumor cells, MEK and RAF inhibitors affect the expression of a common set of genes. PLX4032 inhibits ERK signaling output in mutant BRAF cells, whereas it transiently activates the expression of these genes in tumor cells with wild-type RAF. Thus, PLX4032 inhibits ERK signaling output in a mutant BRAFselective manner. These data explain why the drug selectively inhibits the growth of mutant BRAF tumors and suggest that it will not cause toxicity resulting from the inhibition of ERK signaling in normal cells. This selectivity may lead to a broader therapeutic index and help explain the greater antitumor activity observed with this drug than with MEK inhibitors.

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Section: Methodsmentioning

confidence: 99%

The RAF inhibitor PLX4032 inhibits ERK signaling and tumor cell proliferation in a V600E BRAF-selective manner

Joseph

Pratilas

Poulikakos³

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

423

352

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“…CI-1040 is the first MEK1/2 inhibitor to enter into a clinical trial (63). Despite effective inhibition of the MEK pathway and demonstration of antitumor activity in HCC cell models, its development was halted after phase II trials due to poor clinical efficacy (64,65).…”

Section: Targeting Mekmentioning

confidence: 99%

Targeting the Ras/Raf/MEK/ERK pathway in hepatocellular carcinoma

2017

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Abstract. Although the biological basis of hepatocellular carcinoma (HCC) remains unclear, effective treatments and improvement of the survival rate remain worthwhile research goals. Abnormal protein signaling pathways contributing to uncontrolled cell proliferation, differentiation, survival and apoptosis are biomarkers of the carcinogenic process. Certain mutated components or overexpression of the rat sarcoma virus (Ras)/rapidly accelerated fibrosarcoma (Raf)/mitogen-activated protein kinase kinase (MEK)/extracellular signal-regulated kinase (ERK) signaling pathway are increasingly being studied in HCC carcinogenesis. The present review addresses the effect of the Ras/Raf/MEK/ERK signaling pathway on the pathogenesis of HCC, and provides an update on the preclinical and clinical development of various inhibitors targeting this core signaling pathway, which include various Ras inhibitors, Raf inhibitors and MEK inhibitors for HCC.

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“…5, 6 Inhibitors of MEK have demonstrated efficacy against malignant tumors characterized by mutations in either RAS or Raf in preclinical models, and early development candidates including GSK1120212, 7 AZD6244, 8 and PD0325901 (2) 9 have further demonstrated evidence of activity in the clinical setting as well.…”

mentioning

confidence: 99%

Novel Carboxamide-Based Allosteric MEK Inhibitors: Discovery and Optimization Efforts toward XL518 (GDC-0973)

Rice

Aay

Anand

et al. 2012

ACS Med. Chem. Lett.

144

108

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The ERK/MAP kinase cascade is a key mechanism subject to dysregulation in cancer and is constitutively activated or highly upregulated in many tumor types. Mutations associated with upstream pathway components RAS and Raf occur frequently and contribute to the oncogenic phenotype through activation of MEK and then ERK. Inhibitors of MEK have been shown to effectively block upregulated ERK/MAPK signaling in a range of cancer cell lines and have further demonstrated early evidence of efficacy in the clinic for the treatment of cancer. Guided by structural insight, a strategy aimed at the identification of an optimal diphenylamine-based MEK inhibitor with an improved metabolism and safety profile versus PD-0325901 led to the discovery of development candidate 1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-[(2S)-piperidin-2-yl]azetidin-3-ol (XL518, GDC-0973) (1). XL518 exhibits robust in vitro and in vivo potency and efficacy in preclinical models with sustained duration of action and is currently in early stage clinical trials. KEYWORDS: MAPK pathway, MEK, cancer, kinase inhibitor, XL518, GDC-0973 T he MAPK cascade, or mitogen-activated protein kinase signal transduction pathway, is a mechanism commonly subject to dysregulation in cancer, and constitutive or highly upregulated signaling is a frequent hallmark of oncogenic transformation and progression. Controlled by activation of RAS at the cell surface interior, the subsequent stimulation of Raf and then MEK and ERK serves to regulate a range of key intracellular effectors associated with cell proliferation, 1 invasion, 2 angiogenesis, 3 and apoptotic resistance. 4 Mutated RAS is associated with almost one-third of human cancers, and a majority of malignant melanomas and papillary thyroid cancers harbor B-Raf mutations. 5,6 Inhibitors of MEK have demonstrated efficacy against malignant tumors characterized by mutations in either RAS or Raf in preclinical models, and early development candidates including GSK1120212, In some tumors, activation of both the RAS driven ERK/ MAPK cascade and the PI3K-Akt pathway is observed, resulting in degenerate and convergent oncogenic signals, and upregulation or constitutive PI3K pathway activation is associated with resistance to MEK inhibitor single agent treatment.10 Several combination approaches using inhibitors of mTor, PI3K, Akt, and Raf have more recently been validated in preclinical models and are being pursued clinically. Herein, the discovery of XL518 (GDC-0973) (1), a potent and selective MEK inhibitor, is described. XL518 is currently in early stage clinical testing as both a single agent and in combination with the class I PI3K inhibitor GDC-0941. 11Our goal at the outset was the identification of a potent and selective MEK inhibitor with sustained duration of efficacy suitable for qd dosing and an optimized safety profile relative to clinical precursors. The diphenylamine series disclosed by the Pfizer/Warner Lambert groups served as a starting point for our effort. A key aspect tha...

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The discovery of the benzhydroxamate MEK inhibitors CI-1040 and PD 0325901

Cited by 259 publications

References 17 publications

The RAF inhibitor PLX4032 inhibits ERK signaling and tumor cell proliferation in a V600E BRAF-selective manner

The RAF inhibitor PLX4032 inhibits ERK signaling and tumor cell proliferation in a V600E BRAF-selective manner

Targeting the Ras/Raf/MEK/ERK pathway in hepatocellular carcinoma

Novel Carboxamide-Based Allosteric MEK Inhibitors: Discovery and Optimization Efforts toward XL518 (GDC-0973)

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