NK7-902 diTFA is a selective and orally active CRBN-dependent NEK7 molecular glue degrader with K d values of 1.5 and 2.6 μM for hNEK7 and mNEK7. NK7-902 diTFA fully degrades NEK7 in human primary monocytes and whole blood but only partially inhibits NLRP3 -dependent IL-1β production. NK7-902 diTFA shows activity in murine systems and induces a profound and long-lasting NEK7 degradation but only transiently blocks NLRP3 inflammasome activation. NK7-902 diTFA can be used for the research of inflammation, such as cryopyrin-associated periodic syndromes [1].
In Vivo, NK7-902 diTFA (30-300 mg/kg; p.o.; single dose; 6h/16h pre-LPS challenge) induces dose-dependent NEK7 degradation and corresponding inhibition of NLRP3 inflammasome-mediated IL-1β release in a mouse acute peritonitis model[1]. NK7-902 diTFA (300 mg/kg; p.o.; single dose; 16h pre-LPS challenge) induces robust NEK7 degradation and significant inhibition of NLRP3 inflammasome-mediated IL-1β release in a mouse CAPS model[1]. NK7-902 diTFA (0.2-2 mg/kg; p.o.; single dose) induces profound, long-lasting NEK7 degradation but only transient IL-1β inhibition in non-human primates[1].
In Vitro, NK7-902 diTFA (0.005-10000 nM; 18 h pre-treatment) potently and selectively degrades NEK7 (DC50 = 0.2 nM) in human primary monocytes, with partial, stimulus-dependent inhibition of NLRP3 inflammasome-mediated IL-1β secretion[1]. NK7-902 diTFA (0.009-10000 nM; 18 h) potently degrades NEK7 (DC50 = 1.6 nM) in human PBMCs, with full NLRP3 inflammasome inhibition in most CAPS mutations but partial inhibition in the NEK7T348M mutation[1]. NK7-902 diTFA (0.001-10000 nM; 18 h) potently degrades NEK7 in human whole blood (DC50 = 8.7 nM) and neutrophils, with partial IL-1β inhibition in whole blood but full inhibition in isolated neutrophils[1]. NK7-902 diTFA (1-10000 nM; 18 h) potently degrades NEK7 (DC50 = 54.2 nM) in mouse primary splenocytes in a CRBN-dependent manner[1]. NK7-902 diTFA (0.1-10000 nM; 18 h) potently degrades NEK7 (DC50 = 4.1 nM) in NHP blood in vitro[1]. NK7-902 diTFA (20-411 μg/mL; 96 h) degrades NEK7 in human primary blood lymphocytes without inducing significant chromosomal damage or cell cycle delay[1].
References:
[1]. Sylvain A, et, al. A cereblon (CRBN) molecular glue degrader of NIMA-related kinase 7 (NEK7) reveals a context-dependent role in NLRP3 inflammasome activation. bioRxiv. 2024.11.06.622079.
In Vivo, NK7-902 diTFA (30-300 mg/kg; p.o.; single dose; 6h/16h pre-LPS challenge) induces dose-dependent NEK7 degradation and corresponding inhibition of NLRP3 inflammasome-mediated IL-1β release in a mouse acute peritonitis model[1]. NK7-902 diTFA (300 mg/kg; p.o.; single dose; 16h pre-LPS challenge) induces robust NEK7 degradation and significant inhibition of NLRP3 inflammasome-mediated IL-1β release in a mouse CAPS model[1]. NK7-902 diTFA (0.2-2 mg/kg; p.o.; single dose) induces profound, long-lasting NEK7 degradation but only transient IL-1β inhibition in non-human primates[1].
In Vitro, NK7-902 diTFA (0.005-10000 nM; 18 h pre-treatment) potently and selectively degrades NEK7 (DC50 = 0.2 nM) in human primary monocytes, with partial, stimulus-dependent inhibition of NLRP3 inflammasome-mediated IL-1β secretion[1]. NK7-902 diTFA (0.009-10000 nM; 18 h) potently degrades NEK7 (DC50 = 1.6 nM) in human PBMCs, with full NLRP3 inflammasome inhibition in most CAPS mutations but partial inhibition in the NEK7T348M mutation[1]. NK7-902 diTFA (0.001-10000 nM; 18 h) potently degrades NEK7 in human whole blood (DC50 = 8.7 nM) and neutrophils, with partial IL-1β inhibition in whole blood but full inhibition in isolated neutrophils[1]. NK7-902 diTFA (1-10000 nM; 18 h) potently degrades NEK7 (DC50 = 54.2 nM) in mouse primary splenocytes in a CRBN-dependent manner[1]. NK7-902 diTFA (0.1-10000 nM; 18 h) potently degrades NEK7 (DC50 = 4.1 nM) in NHP blood in vitro[1]. NK7-902 diTFA (20-411 μg/mL; 96 h) degrades NEK7 in human primary blood lymphocytes without inducing significant chromosomal damage or cell cycle delay[1].
References:
[1]. Sylvain A, et, al. A cereblon (CRBN) molecular glue degrader of NIMA-related kinase 7 (NEK7) reveals a context-dependent role in NLRP3 inflammasome activation. bioRxiv. 2024.11.06.622079.