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

被引：126

作者：

Rice, Kenneth D. ^{[1
]}

Aay, Naing ^{[1
]}

Anand, Neel K. ^{[1
]}

Blazey, Charles M. ^{[1
]}

Bowles, Owen J. ^{[1
]}

Bussenius, Joerg ^{[1
]}

Costanzo, Simona ^{[1
]}

Curtis, Jeffry K. ^{[1
]}

Defina, Steven C. ^{[1
]}

Dubenko, Larisa ^{[1
]}

Engst, Stefan ^{[1
]}

Joshi, Anagha A. ^{[1
]}

Kennedy, Abigail R. ^{[1
]}

Kim, Angie I. ^{[1
]}

Koltun, Elena S. ^{[1
]}

Lougheed, Julie C. ^{[1
]}

Manalo, Jean-Claire L. ^{[1
]}

Martini, Jean-Francois ^{[1
]}

Nuss, John M. ^{[1
]}

Peto, Csaba J. ^{[1
]}

Tsang, Tsze H. ^{[1
]}

Yu, Peiwen ^{[1
]}

Johnston, Stuart ^{[1
]}

机构：

[1] Exelixis Inc, San Francisco, CA 94080 USA

来源：

ACS MEDICINAL CHEMISTRY LETTERS | 2012年 / 3卷 / 05期

关键词：

MAPK pathway; MEK; cancer; kinase inhibitor; XL518; GDC-0973; CANCER; CI-1040;

D O I：

10.1021/ml300049d

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

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 in preclinical models with sustained duration of action and is currently in early stage clinical trials. potency and efficacy in preclinical models with sustained duration of action and is currently in early stage clinical trials.

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页码：416 / 421

页数：6

相关论文

共 17 条

[1] Epidermal growth factor induces matrix metalloproteinase-1 (MMP-1) expression and invasion in glioma cell lines via the MAPK pathway [J].

Anand, M. ;

Van Meter, T. E. ;

Fillmore, H. L. .

JOURNAL OF NEURO-ONCOLOGY, 2011, 104 (03) :679-687

[2] The discovery of the benzhydroxamate MEK inhibitors CI-1040 and PD 0325901 [J].

Barrett, Stephen D. ;

Bridges, Alexander J. ;

Dudley, David T. ;

Saltiel, Alan R. ;

Fergus, James H. ;

Flamme, Cathlin M. ;

Delaney, Amy M. ;

Kaufman, Michael ;

LePage, Sophie ;

Leopold, Wilbur R. ;

Przybranowski, Sally A. ;

Sebolt-Leopold, Judith ;

Van Becelaere, Keri ;

Doherty, Annette M. ;

Kennedy, Robert M. ;

Marston, Dan ;

Howard, W. Allen, Jr. ;

Smith, Yvonne ;

Warmus, Joseph S. ;

Tecle, Haile .

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2008, 18 (24) :6501-6504

[3] ALPHA-LITHIOAMINE SYNTHETIC EQUIVALENTS - SYNTHESES OF DIASTEREOISOMERS FROM THE BOC PIPERIDINES [J].

BEAK, P ;

LEE, WK .

JOURNAL OF ORGANIC CHEMISTRY, 1990, 55 (09) :2578-2580

[4] A Phase II, open-label, randomised study to assess the efficacy and safety of the MEK1/2 inhibitor AZD6244 (ARRY-142886) versus capecitabine monotherapy in patients with colorectal cancer who have failed one or two prior chemotherapeutic regimens [J].

Bennouna, Jaafar ;

Lang, Istvan ;

Valladares-Ayerbes, Manuel ;

Boer, Katalin ;

Adenis, Antoine ;

Escudero, Pilar ;

Kim, Tae-You ;

Pover, Gillian M. ;

Morris, Clive D. ;

Douillard, Jean-Yves .

INVESTIGATIONAL NEW DRUGS, 2011, 29 (05) :1021-1028

[5]

Fernandez-Medarde Alberto, 2011, Genes Cancer, V2, P344, DOI 10.1177/1947601911411084

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

Gilmartin, Aidan G. ;

Bleam, Maureen R. ;

Groy, Arthur ;

Moss, Katherine G. ;

Minthorn, Elisabeth A. ;

Kulkarni, Swarupa G. ;

Rominger, Cynthia M. ;

Erskine, Symon ;

Fisher, Kelly E. ;

Yang, Jingsong ;

Zappacosta, Francesca ;

Annan, Roland ;

Sutton, David ;

Laquerre, Sylvie G. .

CLINICAL CANCER RESEARCH, 2011, 17 (05) :989-1000

[7] A Phase II Study of PD-0325901, an Oral MEK Inhibitor, in Previously Treated Patients with Advanced Non-Small Cell Lung Cancer [J].

Haura, Eric B. ;

Ricart, Alejandro D. ;

Larson, Timothy G. ;

Stella, Philip J. ;

Bazhenova, Lyudmila ;

Miller, Vincent A. ;

Cohen, Roger B. ;

Eisenberg, Peter D. ;

Selaru, Paulina ;

Wilner, Keith D. ;

Gadgeel, Shirish M. .

CLINICAL CANCER RESEARCH, 2010, 16 (08) :2450-2457

[8] Intermittent Administration of MEK Inhibitor GDC-0973 plus PI3K Inhibitor GDC-0941 Triggers Robust Apoptosis and Tumor Growth Inhibition [J].

Hoeflich, Klaus P. ;

Merchant, Mark ;

Orr, Christine ;

Chan, Jocelyn ;

Den Otter, Doug ;

Berry, Leanne ;

Kasman, Ian ;

Koeppen, Hartmut ;

Rice, Ken ;

Yang, Nai-Ying ;

Engst, Stefan ;

Johnston, Stuart ;

Friedman, Lori S. ;

Belvin, Marcia .

CANCER RESEARCH, 2012, 72 (01) :210-219

[9]

Johnston S, 2007, AACR NCI EORTC INT C

[10] Hyperactivation of NF-κB via the MEK signaling is indispensable for the inhibitory effect of cAMP on DNA damage-induced cell death [J].

Kloster, Martine M. ;

Naderi, Elin H. ;

Carlsen, Harald ;

Blomhoff, Heidi K. ;

Naderi, Soheil .

MOLECULAR CANCER, 2011, 10