4ARK

CRYSTAL STRUCTURE OF THE CATALYTIC DOMAIN OF HUMAN MAP KINASE KINASE 1 (MEK1) IN COMPLEX WITH A SMALL MOLECULE INHIBITOR AND ADP

Summary for 4ARK

• Entry DOI: 10.2210/pdb4ark/pdb
• Related: 1S9J 4AN2 4AN3 4AN9 4ANB
• Descriptor: DUAL SPECIFICITY MITOGEN-ACTIVATED PROTEIN KINASE KINASE 1, ADENOSINE-5'-DIPHOSPHATE, MAGNESIUM ION, ... (5 entities in total)
• Functional Keywords: transferase, kinase, inhibitor
• Biological source: HOMO SAPIENS (HUMAN)
• Cellular location: Cytoplasm, cytoskeleton, microtubule organizing center, centrosome : Q02750
• Total number of polymer chains: 1
• Total formula weight: 38860.34

Authors

Hartung, I.V.,Hitchcock, M.,Puehler, F.,Neuhaus, R.,Scholz, A.,Hammer, S.,Petersen, K.,Siemeister, G.,Brittain, D.,Hillig, R.C. (deposition date: 2012-04-24, release date: 2013-03-06, Last modification date: 2023-12-20)

Primary citation

Hartung, I.V.,Hitchcock, M.,Puehler, F.,Neuhaus, R.,Scholz, A.,Hammer, S.,Petersen, K.,Siemeister, G.,Brittain, D.,Hillig, R.C.
Optimization of Allosteric Mek Inhibitors - Part 1: Venturing Into Unexplored Sar Territories
Bioorg.Med.Chem.Lett., 23:2384-, 2013

PubMed Abstract: Using PD325901 as a starting point for identifying novel allosteric MEK inhibitors with high cell potency and long-lasting target inhibition in vivo, truncation of its hydroxamic ester headgroup was combined with incorporation of alkyl and aryl ethers at the neighboring ring position. Whereas alkoxy side chains did not yield sufficient levels of cell potency, specifically substituted aryloxy groups allowed for high enzymatic and cellular potencies. Sulfamide 28 was identified as a highly potent MEK inhibitor with nanomolar cell potency against B-RAF (V600E) as well as Ras-mutated cell lines, high metabolic stability and resulting long half-lives. It was efficacious against B-RAF as well as K-Ras driven xenograft models and showed-despite being orally bioavailable and not a P-glycoprotein substrate-much lower brain/plasma exposure ratios than PD325901.

PubMed: 23474388
DOI: 10.1016/J.BMCL.2013.02.028

Experimental method

X-RAY DIFFRACTION (2.6 Å)