4Y5H

Pyridopyrimidinone Derivatives as Potent and Selective c-Jun N-Terminal Kinase (JNK) inhibitors

Summary for 4Y5H

• Entry DOI: 10.2210/pdb4y5h/pdb
• Related: 4Y46
• Descriptor: Mitogen-activated protein kinase 10, 1-(trans-4-{[7-oxo-8-(propan-2-yl)-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl]amino}cyclohexyl)-3-propan-2-ylurea (3 entities in total)
• Functional Keywords: jnk, map kinase, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• Biological source: Homo sapiens (Human)
• Cellular location: Cytoplasm : P53779
• Total number of polymer chains: 1
• Total formula weight: 42648.44

Authors

Park, H. (deposition date: 2015-02-11, release date: 2015-05-06, Last modification date: 2024-02-28)

Primary citation

Zheng, K.,Park, C.M.,Iqbal, S.,Hernandez, P.,Park, H.,LoGrasso, P.V.,Feng, Y.
Pyridopyrimidinone Derivatives as Potent and Selective c-Jun N-Terminal Kinase (JNK) Inhibitors.
Acs Med.Chem.Lett., 6:413-418, 2015

PubMed Abstract: A novel series of 2-aminopyridopyrimidinone based JNK (c-jun N-terminal kinase) inhibitors were discovered and developed. Structure-activity relationships (SARs) were systematically developed utilizing biochemical and cell based assays and in vitro and in vivo drug metabolism and pharmacokinetic (DMPK) studies. Through the optimization of lead compound 1, several potent and selective JNK inhibitors with high oral bioavailability were developed. Inhibitor 13 was a potent JNK3 inhibitor (IC50 = 15 nM), had high selectivity against p38 (IC50 > 10 μM), had high potency in functional cell based assays, and had high stability in human liver microsome (t 1/2 = 76 min), a clean CYP-450 inhibition profile, and excellent oral bioavailability (%F = 87). Moreover, cocrystal structures of compounds 13 and 22 in JNK3 were solved at 2.0 Å. These structures elucidated the binding mode (Type-I binding) and can pave the way for further inhibitor design of this pyridopyrimidinone scaffold for JNK inhibition.

PubMed: 25893042
DOI: 10.1021/ml500474d

Experimental method

X-RAY DIFFRACTION (2.055 Å)