|3eqb, resolution 2.62Å ()|
|Gene:||MAP2K1, MEK1, PRKMK1 (Homo sapiens)|
|Related:|| 1s9j, 2p55, 1s9i
X-ray structure of the human mitogen-activated protein kinase kinase 1 (MEK1) in a complex with ligand and MgATP
This paper reports a second generation MEK inhibitor. The previously reported potent and efficacious MEK inhibitor, PD-184352 (CI-1040), contains an integral hydroxamate moiety. This compound suffered from less than ideal solubility and metabolic stability. An oxadiazole moiety behaves as a bioisostere for the hydroxamate group, leading to a more metabolically stable and efficacious MEK inhibitor.
2-Alkylamino- and alkoxy-substituted 2-amino-1,3,4-oxadiazoles-O-Alkyl benzohydroxamate esters replacements retain the desired inhibition and selectivity against MEK (MAP ERK kinase)., Warmus JS, Flamme C, Zhang LY, Barrett S, Bridges A, Chen H, Gowan R, Kaufman M, Sebolt-Leopold J, Leopold W, Merriman R, Ohren J, Pavlovsky A, Przybranowski S, Tecle H, Valik H, Whitehead C, Zhang E, Bioorg Med Chem Lett. 2008 Dec 1;18(23):6171-4. Epub 2008 Oct 7. PMID:18951019
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
[MP2K1_HUMAN] Defects in MAP2K1 are a cause of cardiofaciocutaneous syndrome (CFC syndrome) [MIM:115150]; also known as cardio-facio-cutaneous syndrome. CFC syndrome is characterized by a distinctive facial appearance, heart defects and mental retardation. Heart defects include pulmonic stenosis, atrial septal defects and hypertrophic cardiomyopathy. Some affected individuals present with ectodermal abnormalities such as sparse, friable hair, hyperkeratotic skin lesions and a generalized ichthyosis-like condition. Typical facial features are similar to Noonan syndrome. They include high forehead with bitemporal constriction, hypoplastic supraorbital ridges, downslanting palpebral fissures, a depressed nasal bridge, and posteriorly angulated ears with prominent helices. The inheritance of CFC syndrome is autosomal dominant.
[MP2K1_HUMAN] 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, leading to 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.
About this Structure
- Warmus JS, Flamme C, Zhang LY, Barrett S, Bridges A, Chen H, Gowan R, Kaufman M, Sebolt-Leopold J, Leopold W, Merriman R, Ohren J, Pavlovsky A, Przybranowski S, Tecle H, Valik H, Whitehead C, Zhang E. 2-Alkylamino- and alkoxy-substituted 2-amino-1,3,4-oxadiazoles-O-Alkyl benzohydroxamate esters replacements retain the desired inhibition and selectivity against MEK (MAP ERK kinase). Bioorg Med Chem Lett. 2008 Dec 1;18(23):6171-4. Epub 2008 Oct 7. PMID:18951019 doi:10.1016/j.bmcl.2008.10.015
- Spicer JA, Rewcastle GW, Kaufman MD, Black SL, Plummer MS, Denny WA, Quin J 3rd, Shahripour AB, Barrett SD, Whitehead CE, Milbank JB, Ohren JF, Gowan RC, Omer C, Camp HS, Esmaeil N, Moore K, Sebolt-Leopold JS, Pryzbranowski S, Merriman RL, Ortwine DF, Warmus JS, Flamme CM, Pavlovsky AG, Tecle H. 4-anilino-5-carboxamido-2-pyridone derivatives as noncompetitive inhibitors of mitogen-activated protein kinase kinase. J Med Chem. 2007 Oct 18;50(21):5090-102. Epub 2007 Sep 19. PMID:17880056 doi:10.1021/jm0704548
- Ohren JF, Chen H, Pavlovsky A, Whitehead C, Zhang E, Kuffa P, Yan C, McConnell P, Spessard C, Banotai C, Mueller WT, Delaney A, Omer C, Sebolt-Leopold J, Dudley DT, Leung IK, Flamme C, Warmus J, Kaufman M, Barrett S, Tecle H, Hasemann CA. Structures of human MAP kinase kinase 1 (MEK1) and MEK2 describe novel noncompetitive kinase inhibition. Nat Struct Mol Biol. 2004 Dec;11(12):1192-7. Epub 2004 Nov 14. PMID:15543157 doi:10.1038/nsmb859
- ↑ Liu X, Yan S, Zhou T, Terada Y, Erikson RL. The MAP kinase pathway is required for entry into mitosis and cell survival. Oncogene. 2004 Jan 22;23(3):763-76. PMID:14737111 doi:10.1038/sj.onc.1207188
- ↑ Burgermeister E, Chuderland D, Hanoch T, Meyer M, Liscovitch M, Seger R. Interaction with MEK causes nuclear export and downregulation of peroxisome proliferator-activated receptor gamma. Mol Cell Biol. 2007 Feb;27(3):803-17. Epub 2006 Nov 13. PMID:17101779 doi:10.1128/MCB.00601-06