NK7-902

NK7-902 is a valuable chemical probe (degrader) to study NEK7-mediated NLRP3 biology. In contrast to other tool compounds NK7-902 not only degrades human and NHP but also mouse protein. In addition, its oral bioavailability allows studies in vivo. The good selectivity was confirmed in a proteomics analysis in human primary monocytes.

NK7-902 is a highly potent, selective CRBN-recruiting molecular glue degrader of NIMA-related kinase 7 (NEK7) with sub‑nanomolar DC50 in human primary monocytes: DC50 ≈ 0.2 nM with Dmax > 95% NEK7 degradation after 18 h. Similar potency (single digit DC50) were observed also in THP‑1 cells, Human PBMCs, neutrophils, and whole blood leukocytes. A slightly lower potency was observed in mouse splenocytes (60 nM DC50). Selectivity was determined by MS-proteomics at 1uM conc. after 18 h treatment of iPS cells and Human primary monocytes. The only off targets were SALL3, FIZ1 and IKZF4 which were depleted to lower extent. Mouse: oral NK7‑902 causes dose‑dependent NEK7 degradation in spleen (maximal at 300 mg/kg) Cynomolgus monkey: single oral doses of 0.2 and 2 mg/kg induced 70 and 95% NEK7 degradation in blood sustained for 48–72 h. NK7‑902 showed moderate clearance (1 mg/kg, IV) and 49.7% bioavailbility (2 mg/kg, PO). Negative control wasn't published but its expected that methylation of the imid motif would lead to the inactive analogue. In summary, NK7‑902 is excellent chemical probe for cellular as well as in vivo application. It has a couple of weaker off targets which should be taken into account. Chemically distinct NEK7 glue degrader LC-04-045 has been published recently, which can serve as great orthogonal tool compound.