Inhibition of NF-κB inducing kinase (NIK) has been pursued as a promising therapeutic target for autoimmune disorders due to its highly regulated role in key steps of the NF-κB signaling pathway. Previously reported NIK inhibitors from our group were shown to be potent, selective, and efficacious, but had higher human dose projections than desirable for immunology indications. Herein we report the clearance-driven optimization of a NIK inhibitor guided by metabolite identification studies and structure-based drug design. This led to the identification of an azabicyclo[3.1.0] hexanone motif that attenuated in vitro and in vivo clearance while maintaining NIK potency and increasing selectivity over other kinases, resulting in a greater than ten-fold reduction in predicted human dose.
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Medicinal Chemistry,
Articles & Whitepapers,
ADME/DMPK,
In vitro Biology,
Immunology & Inflammation
Originally presented in Science Translational Medicine, this article co-written with Merck & Co. presents a set of bifunctional HIV therapies, dubbed targeted activator of cell kill (TACK) molecules, that were optimized for simultaneous antiviral activity and selective elimination of infected CD4+ T cells from HIV-1 patients.
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Structural Biology & Protein Science,
Immunology & Inflammation
Mycobacterium tuberculosis (Mtb), the etiological agent of tuberculosis, kills 1.5 to 1.7 million people every year. Macrophages are Mtb’s main host cells and their inflammatory response is an essential component of the host defense against Mtb. However, Mtb is able to circumvent the macrophages’ defenses by triggering an inappropriate inflammatory response. Understanding macrophage interactions with Mtb is crucial to develop strategies to control tuberculosis. The present study aims to determine the inflammatory response transcriptome and miRNome of human macrophages infected with the virulent H37Rv Mtb strain, to identify macrophage genetic networks specifically modulated by Mtb virulence.
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Medicinal Chemistry,
Articles & Whitepapers,
In vitro Biology,
Anti-Infectives,
Immunology & Inflammation
