SUMMARY OF INVENTION
Inflammasomes, including NLRP1, are multiprotein complexes that trigger an inflammatory form of cell death called pyroptosis in response to intracellular pathogen and danger signals, thereby functioning as key regulators of the innate immune system. Aberrant activation of NLRP1 has been implicated in a host of disorders, including skin inflammatory syndromes, skin cancer predisposition, Alzheimer’s disease, and multiple sclerosis. However, therapeutic strategies to target NLRP1 have not been at the forefront of development, in part due to the lack of clarity surrounding the molecular mechanism responsible for NLRP1 activation.
MSK investigators have elucidated the molecular mechanism underlying the activation of the murine NLRP1 paralog, NLRP1B, using genome-wide CRISPR/Cas9 screens in combination with biochemical experiments. Specifically, they demonstrate that proteasome-mediated N-terminal degradation is the central mechanism of NLRP1B inflammasome activation. Consistent with this finding, investigators show that proteasome inhibitors, including bortezomib, can prevent NLRP1B degradation induced by the anthrax lethal factor metalloprotease and a small molecule DPP8/9 inhibitor, both activators of the NLRP1B inflammasome. Similarly, proteasome inhibitors block human NLRP1 (and CARD8, a homolog of NLRP1) activation caused by either germline mutation or pathogenic stimuli.
- Inflammasomes increasingly recognized for their role in various diseases with unmet medical need
- This invention provides a method for targeting the NLRP1 inflammasome, for which no targeted drugs currently exist
- Method could be moved into preclinical studies in the near-term given existing proteasome inhibitors
Broad market potential given the association of NLRP1 with multiple types of disease
Provisional application 62/794,456 filed on January 18, 2019
Chui et al. (2019) N-terminal degradation activates the NLRP1B inflammasome. Science (PubMed link)
Daniel Bachovchin Ph.D., Laboratory Head, Chemical Biology Program, Sloan Kettering Institute, MSK
Lisa Kennedy, PhD