5IH9

MELK in complex with NVS-MELK8A

Summary for 5IH9

• Entry DOI: 10.2210/pdb5ih9/pdb
• Related: 5HIA 5HIC 5IH8
• Descriptor: Maternal embryonic leucine zipper kinase, 1-methyl-4-[4-(4-{3-[(piperidin-4-yl)methoxy]pyridin-4-yl}-1H-pyrazol-1-yl)phenyl]piperazine (3 entities in total)
• Functional Keywords: kinase uba domain inhibitor, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• Biological source: Homo sapiens (Human)
• Cellular location: Cell membrane ; Peripheral membrane protein : Q14680
• Total number of polymer chains: 1
• Total formula weight: 39391.64

Authors

Sprague, E.R.,Puleo, D.E. (deposition date: 2016-02-29, release date: 2016-06-01, Last modification date: 2024-03-06)

Primary citation

Toure, B.B.,Giraldes, J.,Smith, T.,Sprague, E.R.,Wang, Y.,Mathieu, S.,Chen, Z.,Mishina, Y.,Feng, Y.,Yan-Neale, Y.,Shakya, S.,Chen, D.,Meyer, M.,Puleo, D.,Brazell, J.T.,Straub, C.,Sage, D.,Wright, K.,Yuan, Y.,Chen, X.,Duca, J.,Kim, S.,Tian, L.,Martin, E.,Hurov, K.,Shao, W.
Toward the Validation of Maternal Embryonic Leucine Zipper Kinase: Discovery, Optimization of Highly Potent and Selective Inhibitors, and Preliminary Biology Insight.
J.Med.Chem., 59:4711-4723, 2016

PubMed Abstract: MELK kinase has been implicated in playing an important role in tumorigenesis. Our previous studies suggested that MELK is involved in the regulation of cell cycle and its genetic depletion leads to growth inhibition in a subset of high MELK-expressing basal-like breast cancer cell lines. Herein we describe the discovery and optimization of novel MELK inhibitors 8a and 8b that recapitulate the cellular effects observed by short hairpin ribonucleic acid (shRNA)-mediated MELK knockdown in cellular models. We also discovered a novel fluorine-induced hydrophobic collapse that locked the ligand in its bioactive conformation and led to a 20-fold gain in potency. These novel pharmacological inhibitors achieved high exposure in vivo and were well tolerated, which may allow further in vivo evaluation.

PubMed: 27187609
DOI: 10.1021/acs.jmedchem.6b00052

Experimental method

X-RAY DIFFRACTION (1.79 Å)