title: Inhibiting NF-κB-inducing kinase (NIK): discovery, structure-based design, synthesis, structure-activity relationship, and co-crystal structures.
abstract: The discovery, structure-based design, synthesis, and optimization of NIK inhibitors are described. Our work began with an HTS hit, imidazopyridinyl pyrimidinamine 1. We utilized homology modeling and conformational analysis to optimize the indole scaffold leading to the discovery of novel and potent conformationally constrained inhibitors such as compounds 25 and 28. Compounds 25 and 31 were co-crystallized with NIK kinase domain to provide structural insights.
authors: Amgen Inc., 1120 Veterans Boulevard, South San Francisco, CA 94080, USA. kli@amgen.com
authors: Kexue
authors: K
authors: Li
authors: Lawrence R
authors: LR
authors: McGee
authors: Ben
authors: B
authors: Fisher
authors: Athena
authors: A
authors: Sudom
authors: Jinsong
authors: J
authors: Liu
authors: Steven M
authors: SM
authors: Rubenstein
authors: Mohmed K
authors: MK
authors: Anwer
authors: Timothy D
authors: TD
authors: Cushing
authors: Youngsook
authors: Y
authors: Shin
authors: Merrill
authors: M
authors: Ayres
authors: Fei
authors: F
authors: Lee
authors: John
authors: J
authors: Eksterowicz
authors: Paul
authors: P
authors: Faulder
authors: Bohdan
authors: B
authors: Waszkowycz
authors: Olga
authors: O
authors: Plotnikova
authors: Ellyn
authors: E
authors: Farrelly
authors: Shou-Hua
authors: SH
authors: Xiao
authors: Guoqing
authors: G
authors: Chen
authors: Zhulun
authors: Z
authors: Wang
mesh_terms: D000480:Alkynes / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D000588:Amines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D015195:Drug Design; D019073:HT29 Cells; D006801:Humans; D006860:Hydrogen Bonding; D007093:Imidazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D008958:Models, Molecular; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000737:chemistry; D011725:Pyridines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D011743:Pyrimidines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship; D000097782:NF-kappaB-Inducing Kinase
chemical_list: D000480:Alkynes; D000588:Amines; D007093:Imidazoles; D047428:Protein Kinase Inhibitors; D017346:Protein Serine-Threonine Kinases; D011725:Pyridines; D011743:Pyrimidines; D000097782:NF-kappaB-Inducing Kinase