2. Academic Validation
  3. Scaffold-Hopping Approach To Discover Potent, Selective, and Efficacious Inhibitors of NF-κB Inducing Kinase

Scaffold-Hopping Approach To Discover Potent, Selective, and Efficacious Inhibitors of NF-κB Inducing Kinase

  • J Med Chem. 2018 Aug 9;61(15):6801-6813. doi: 10.1021/acs.jmedchem.8b00678.
Nicole Blaquiere 1,  Georgette M Castanedo 1,  Jason D Burch 1,  Leonid M Berezhkovskiy 1,  Hans Brightbill 1,  Suzanne Brown 1,  Connie Chan 1,  Po-Chang Chiang 1,  James J Crawford 1,  Teresa Dong 1,  Peter Fan 1,  Jianwen Feng 1,  Nico Ghilardi 1,  Robert Godemann 2,  Emily Gogol 1,  Alice Grabbe 2,  Alison J Hole 2,  Baihua Hu 3,  Sarah G Hymowitz 1,  Moulay Hicham Alaoui Ismaili 1,  Hoa Le 1,  Patrick Lee 1,  Wyne Lee 1,  Xingyu Lin 3,  Ning Liu 1,  Paul A McEwan 2,  Brent McKenzie 1,  Hernani L Silvestre 2,  Eric Suto 1,  Swathi Sujatha-Bhaskar 1,  Guosheng Wu 3,  Lawren C Wu 1,  Yamin Zhang 3,  Zoe Zhong 1,  Steven T Staben 1
Affiliations

Affiliations

  • 1 Genentech, Inc. , 1 DNA Way , South San Francisco , California 94080 , United States.
  • 2 Evotec AG , Manfred Eigen Campus, Essener Bogen , Hamburg 22419 , Germany.
  • 3 Pharmaron Beijing Co., Ltd. , 6 Taihe Road, BDA , Beijing 100176 , P. R. China.
PMID: 29940120 DOI: 10.1021/acs.jmedchem.8b00678
Abstract

NF-κB-inducing kinase (NIK) is a protein kinase central to the noncanonical NF-κB pathway downstream from multiple TNF Receptor family members, including BAFF, which has been associated with B cell survival and maturation, dendritic cell activation, secondary lymphoid organ development, and bone metabolism. We report herein the discovery of lead chemical series of NIK inhibitors that were identified through a scaffold-hopping strategy using structure-based design. Electronic and steric properties of lead compounds were modified to address glutathione conjugation and amide hydrolysis. These highly potent compounds exhibited selective inhibition of LTβR-dependent p52 translocation and transcription of NF-κB2 related genes. Compound 4f is shown to have a favorable pharmacokinetic profile across species and to inhibit BAFF-induced B cell survival in vitro and reduce splenic marginal zone B cells in vivo.

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