Biochemical and Cellular Profile of NIK Inhibitors with Long Residence Times.
Petro HalkowyczCharles E GrimshawWalter KeungPaul TanisChris ProffittKim PeacockRon de JongMark SabatUrmi BanerjeeJacques ErmolieffPublished in: SLAS discovery : advancing life sciences R & D (2020)
Two different signaling pathways lead to the activation of the transcription factor NF-κB, initiating distinct biological responses: The canonical NF-κB pathway activation has been implicated in host immunity and inflammatory responses, whereas the noncanonical pathway activation has been involved in lymphoid organ development and B-cell maturation, as well as in the development of chronic inflammatory diseases and some hematologic cancers. The NF-κB-inducing kinase (NIK) is a cytoplasmic Ser/Thr kinase and is a key regulator of the noncanonical pathway. NIK activation results in the processing of the p100 subunit to p52, leading to the formation of the RelB/p52 complex and noncanonical pathway activation. Because of its role in the development of lymphoid malignancies, this kinase has always been considered as an attractive target for the treatment of certain types of cancers and immune diseases. We at Takeda have pursued a drug discovery program to identify small-molecule inhibitors against NIK. This report provides an overview of the data generated from our screening campaign using a small fragment library. Most importantly, we also provide a kinetic analysis of published compounds and chemical series developed at Takeda that are associated with a slow tight-binding mechanism and excellent cellular potency.
Keyphrases
- signaling pathway
- transcription factor
- small molecule
- drug discovery
- pi k akt
- oxidative stress
- lps induced
- nuclear factor
- randomized controlled trial
- tyrosine kinase
- systematic review
- machine learning
- inflammatory response
- cell proliferation
- electronic health record
- blood brain barrier
- immune response
- deep learning
- smoking cessation