4OBO

MAP4K4 in complex with inhibitor (compound 22), 6-(3-CHLOROPHENYL)QUINAZOLIN-4-AMINE

Summary for 4OBO

• Entry DOI: 10.2210/pdb4obo/pdb
• Related: 4OBP 4OBQ
• Descriptor: Mitogen-activated protein kinase kinase kinase kinase 4, 2-(N-MORPHOLINO)-ETHANESULFONIC ACID, SODIUM ION, ... (5 entities in total)
• Functional Keywords: kinase, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• Biological source: Homo sapiens (human)
• Cellular location: Cytoplasm : O95819
• Total number of polymer chains: 2
• Total formula weight: 76237.07

Authors

Harris, S.F.,Wu, P.,Coons, M. (deposition date: 2014-01-07, release date: 2014-04-23, Last modification date: 2024-02-28)

Primary citation

Crawford, T.D.,Ndubaku, C.O.,Chen, H.,Boggs, J.W.,Bravo, B.J.,Delatorre, K.,Giannetti, A.M.,Gould, S.E.,Harris, S.F.,Magnuson, S.R.,McNamara, E.,Murray, L.J.,Nonomiya, J.,Sambrone, A.,Schmidt, S.,Smyczek, T.,Stanley, M.,Vitorino, P.,Wang, L.,West, K.,Wu, P.,Ye, W.
Discovery of Selective 4-Amino-pyridopyrimidine Inhibitors of MAP4K4 Using Fragment-Based Lead Identification and Optimization.
J.Med.Chem., 57:3484-3493, 2014

PubMed Abstract: Mitogen-activated protein kinase kinase kinase kinase 4 (MAP4K4) is a serine/threonine kinase implicated in the regulation of many biological processes. A fragment-based lead discovery approach was used to generate potent and selective MAP4K4 inhibitors. The fragment hit pursued in this article had excellent ligand efficiency (LE), an important attribute for subsequent successful optimization into drug-like lead compounds. The optimization efforts eventually led us to focus on the pyridopyrimidine series, from which 6-(2-fluoropyridin-4-yl)pyrido[3,2-d]pyrimidin-4-amine (29) was identified. This compound had low nanomolar potency, excellent kinase selectivity, and good in vivo exposure, and demonstrated in vivo pharmacodynamic effects in a human tumor xenograft model.

PubMed: 24673130
DOI: 10.1021/jm500155b

Experimental method

X-RAY DIFFRACTION (2.1 Å)