Target Information
| Target General Information | Top | |||||
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| Target ID |
T23003
(Former ID: TTDI01775)
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| Target Name |
MAPK/ERK kinase kinase (MAP3K)
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| Gene Name |
NO-GeName
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| Target Type |
Successful target
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[1] | ||||
| Disease | [+] 1 Target-related Diseases | + | ||||
| 1 | Melanoma [ICD-11: 2C30] | |||||
| Function |
Dual specificity protein kinase which acts as an essential component of the MAP kinase signal transduction pathway. Binding of extracellular ligands such as growth factors, cytokines and hormones to their cell-surface receptors activates RAS and this initiates RAF1 activation. RAF1 then further activates the dual-specificity protein kinases MAP2K1/MEK1 and MAP2K2/MEK2. Both MAP2K1/MEK1 and MAP2K2/MEK2 function specifically in the MAPK/ERK cascade, and catalyze the concomitant phosphorylation of a threonine and a tyrosine residue in a Thr-Glu-Tyr sequence located in the extracellular signal-regulated kinases MAPK3/ERK1 and MAPK1/ERK2, leadingto their activation and further transduction of the signal within the MAPK/ERK cascade. Depending on the cellular context, this pathway mediates diverse biological functions such as cell growth, adhesion, survival and differentiation, predominantly through the regulation of transcription, metabolism and cytoskeletal rearrangements. One target of the MAPK/ERK cascade is peroxisome proliferator- activated receptor gamma (PPARG), a nuclear receptor that promotes differentiation and apoptosis. MAP2K1/MEK1 has been shown to export PPARG from the nucleus. The MAPK/ERK cascade is also involved in the regulation of endosomal dynamics, including lysosome processing and endosome cycling through the perinuclear recycling compartment (PNRC), as well as in the fragmentation of the Golgi apparatus during mitosis.
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| BioChemical Class |
Kinase
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| UniProt ID | ||||||
| Drugs and Modes of Action | Top | |||||
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| Approved Drug(s) | [+] 2 Approved Drugs | + | ||||
| 1 | ARRY-162 | Drug Info | Approved | Melanoma | [2] | |
| 2 | Trametinib | Drug Info | Approved | Melanoma | [1], [3] | |
| Clinical Trial Drug(s) | [+] 11 Clinical Trial Drugs | + | ||||
| 1 | BAY 86-9766 | Drug Info | Phase 3 | Solid tumour/cancer | [4], [5] | |
| 2 | Selumetinib | Drug Info | Phase 3 | Melanoma | [6] | |
| 3 | E6201 | Drug Info | Phase 2 | Psoriasis vulgaris | [7], [8] | |
| 4 | MSC1936369B | Drug Info | Phase 2 | Colorectal cancer | [9], [10] | |
| 5 | PD-0325901 | Drug Info | Phase 2 | Breast cancer | [11], [12] | |
| 6 | RO-5126766 | Drug Info | Phase 2 | Ovarian cancer | [13] | |
| 7 | WX-554 | Drug Info | Phase 1/2 | Solid tumour/cancer | [14] | |
| 8 | ARRY-300 | Drug Info | Phase 1 | Solid tumour/cancer | [15] | |
| 9 | BI-847325 | Drug Info | Phase 1 | Solid tumour/cancer | [16] | |
| 10 | RG7304 | Drug Info | Phase 1 | Solid tumour/cancer | [17] | |
| 11 | TAK-733 | Drug Info | Phase 1 | Solid tumour/cancer | [18] | |
| Discontinued Drug(s) | [+] 3 Discontinued Drugs | + | ||||
| 1 | AZD8330 | Drug Info | Discontinued in Phase 1 | Solid tumour/cancer | [19], [20] | |
| 2 | RG-7167 | Drug Info | Discontinued in Phase 1 | Solid tumour/cancer | [21] | |
| 3 | RO-4987655 | Drug Info | Discontinued in Phase 1 | Solid tumour/cancer | [21] | |
| Mode of Action | [+] 2 Modes of Action | + | ||||
| Modulator | [+] 14 Modulator drugs | + | ||||
| 1 | ARRY-162 | Drug Info | [22] | |||
| 2 | Trametinib | Drug Info | [1] | |||
| 3 | BAY 86-9766 | Drug Info | [23], [24] | |||
| 4 | Selumetinib | Drug Info | [25] | |||
| 5 | E6201 | Drug Info | [26] | |||
| 6 | MSC1936369B | Drug Info | [10] | |||
| 7 | PD-0325901 | Drug Info | [22] | |||
| 8 | RO-5126766 | Drug Info | [27] | |||
| 9 | WX-554 | Drug Info | [22] | |||
| 10 | ARRY-300 | Drug Info | [28] | |||
| 11 | BI-847325 | Drug Info | [29] | |||
| 12 | TAK-733 | Drug Info | [22] | |||
| 13 | AZD8330 | Drug Info | [22] | |||
| 14 | RO-4987655 | Drug Info | [22] | |||
| Inhibitor | [+] 8 Inhibitor drugs | + | ||||
| 1 | RG7304 | Drug Info | [30] | |||
| 2 | RG-7167 | Drug Info | [31] | |||
| 3 | CIP-137401 | Drug Info | [31] | |||
| 4 | G-573 | Drug Info | [31] | |||
| 5 | MEK inhibitor I | Drug Info | [32] | |||
| 6 | NSC-686549 | Drug Info | [33] | |||
| 7 | RO-4920506 | Drug Info | [31] | |||
| 8 | SL-327 | Drug Info | [33] | |||
| Drug Property Profile of Target | Top | |
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| (1) Molecular Weight (mw) based Drug Clustering | (2) Octanol/Water Partition Coefficient (xlogp) based Drug Clustering | |
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| (3) Hydrogen Bond Donor Count (hbonddonor) based Drug Clustering | (4) Hydrogen Bond Acceptor Count (hbondacc) based Drug Clustering | |
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| (5) Rotatable Bond Count (rotbonds) based Drug Clustering | (6) Topological Polar Surface Area (polararea) based Drug Clustering | |
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| "RO5" indicates the cutoff set by lipinski's rule of five; "D123AB" colored in GREEN denotes the no violation of any cutoff in lipinski's rule of five; "D123AB" colored in PURPLE refers to the violation of only one cutoff in lipinski's rule of five; "D123AB" colored in BLACK represents the violation of more than one cutoffs in lipinski's rule of five | ||
| Co-Targets | Top | |||||
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| Co-Targets | ||||||
| References | Top | |||||
|---|---|---|---|---|---|---|
| REF 1 | Radium 223 dichloride for prostate cancer treatment. Drug Des Devel Ther. 2017 Sep 6;11:2643-2651. | |||||
| REF 2 | 2018 FDA drug approvals.Nat Rev Drug Discov. 2019 Feb;18(2):85-89. | |||||
| REF 3 | URL: http://www.guidetopharmacology.org Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Ligand id: 6495). | |||||
| REF 4 | URL: http://www.guidetopharmacology.org Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Ligand id: 7942). | |||||
| REF 5 | Allosteric MEK1/2 inhibitor refametinib (BAY 86-9766) in combination with sorafenib exhibits antitumor activity in preclinical murine and rat models of hepatocellular carcinoma. Neoplasia. 2013 Oct;15(10):1161-71. | |||||
| REF 6 | ClinicalTrials.gov (NCT01933932) Assess Efficacy & Safety of Selumetinib in Combination With Docetaxel in Patients Receiving 2nd Line Treatment for v-Ki-ras2 Kirsten Rat Sarcoma Viral Oncogene Homolog (KRAS) Positive NSCLC (SELECT-1) | |||||
| REF 7 | URL: http://www.guidetopharmacology.org Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Ligand id: 7836). | |||||
| REF 8 | ClinicalTrials.gov (NCT02418000) A Study of E6201 for the Treatment of Advanced Hematologic Malignancies With FLT3 Mutation. U.S. National Institutes of Health. | |||||
| REF 9 | URL: http://www.guidetopharmacology.org Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Ligand id: 7872). | |||||
| REF 10 | Antitumor activity of pimasertib, a selective MEK 1/2 inhibitor, in combination with PI3K/mTOR inhibitors or with multi-targeted kinase inhibitors in pimasertib-resistant human lung and colorectal cancer cells. Int J Cancer. 2013 Nov;133(9):2089-101. | |||||
| REF 11 | URL: http://www.guidetopharmacology.org Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Ligand id: 7935). | |||||
| REF 12 | Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800020671) | |||||
| REF 13 | ClinicalTrials.gov (NCT04625270) A Study of VS-6766 v. VS-6766 + Defactinib in Recurrent Low-Grade Serous Ovarian Cancer With and Without a KRAS Mutation. U.S. National Institutes of Health. | |||||
| REF 14 | ClinicalTrials.gov (NCT01581060) Phase I/II Dose-escalation Study to Investigate Safety and Pharmacokinetics/ Pharmacodynamics of WX-554 in Patients With Solid Tumours. U.S. National Institutes of Health. | |||||
| REF 15 | ClinicalTrials.gov (NCT00828165) A Safety Study of ARRY-300 in Healthy Subjects. U.S. National Institutes of Health. | |||||
| REF 16 | ClinicalTrials.gov (NCT01324830) Monotherapy Dose Finding With BI 847325 in Solid Tumours. U.S. National Institutes of Health. | |||||
| REF 17 | Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800029782) | |||||
| REF 18 | ClinicalTrials.gov (NCT00948467) Study of TAK-733 in Adult Patients With Advanced Nonhematologic Malignancies. U.S. National Institutes of Health. | |||||
| REF 19 | URL: http://www.guidetopharmacology.org Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Ligand id: 8474). | |||||
| REF 20 | Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800026144) | |||||
| REF 21 | Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800028214) | |||||
| REF 22 | MEK and the inhibitors: from bench to bedside. J Hematol Oncol. 2013; 6: 27. | |||||
| REF 23 | RDEA119/BAY 869766: a potent, selective, allosteric inhibitor of MEK1/2 for the treatment of cancer.Cancer Res.2009 Sep 1;69(17):6839-47. | |||||
| REF 24 | Antitumour activity of a potent MEK inhibitor RDEA119/BAY 869766 combined with rapamycin in human orthotopic primary pancreatic cancer xenografts.BMC Cancer.2010 Sep 28;10:515. | |||||
| REF 25 | Intrinsic resistance to selumetinib, a selective inhibitor of MEK1/2, by cAMP-dependent protein kinase A activation in human lung and colorectal cancer cells.Br J Cancer.2012 May 8;106(10):1648-59. | |||||
| REF 26 | E6201, a novel kinase inhibitor of mitogen-activated protein kinase/extracellular signal-regulated kinase kinase-1 and mitogen-activated protein kinase/extracellular signal-regulated kinase kinase kinase-1: in vivo effects on cutaneous inflammatory responses by topical administration. J Pharmacol Exp Ther. 2010 Oct;335(1):23-31. | |||||
| REF 27 | The dual RAF/MEK inhibitor CH5126766/RO5126766 may be a potential therapy for RAS-mutated tumor cells.PLoS One.2014 Nov 25;9(11):e113217. | |||||
| REF 28 | MEK and the inhibitors: from bench to bedside. J Hematol Oncol. 2013 Apr 12;6:27. | |||||
| REF 29 | doi: 10.1158/1535-7163.TARG-13-B281 | |||||
| REF 30 | Clinical pipeline report, company report or official report of Roche. | |||||
| REF 31 | URL: http://www.guidetopharmacology.org Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Target id: 2063). | |||||
| REF 32 | Beyond U0126. Dianion chemistry leading to the rapid synthesis of a series of potent MEK inhibitors. Bioorg Med Chem Lett. 2004 Mar 22;14(6):1483-6. | |||||
| REF 33 | A systematic interaction map of validated kinase inhibitors with Ser/Thr kinases. Proc Natl Acad Sci U S A. 2007 Dec 18;104(51):20523-8. | |||||
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