Download MendeleyStructure-Based Design of Type II Inhibitors Applied to Maternal Embryonic Leucine Zipper Kinase.
Johnson, C.N., Adelinet, C., Berdini, V., Beke, L., Bonnet, P., Brehmer, D., Calo, F., Coyle, J.E., Day, P.J., Frederickson, M., Freyne, E.J.E., Gilissen, R.A.H.J., Hamlett, C.C.F., Howard, S., Meerpoel, L., Mevellec, L., Mcmenamin, R., Pasquier, E., Patel, S., Rees, D.C., Linders, J.T.M.(2015) ACS Med Chem Lett 6: 31
- PubMed: 25589926
- DOI: https://doi.org/10.1021/ml5001273
- Primary Citation of Related Structures:
4UMT, 4UMU - PubMed Abstract:
A novel Type II kinase inhibitor chemotype has been identified for maternal embryonic leucine zipper kinase (MELK) using structure-based ligand design. The strategy involved structural characterization of an induced DFG-out pocket by protein-ligand X-ray crystallography and incorporation of a slender linkage capable of bypassing a large gate-keeper residue, thus enabling design of molecules accessing both hinge and induced pocket regions. Optimization of an initial hit led to the identification of a low-nanomolar, cell-penetrant Type II inhibitor suitable for use as a chemical probe for MELK.
Organizational Affiliation:
Astex Pharmaceuticals , 436 Cambridge Science Park, Milton Road, Cambridge CB4 0QA, United Kingdom.
