2-[[(苯甲酰基氨基)硫代甲酰]氨基]-4,7-二氢-5,5-二甲基-5H-噻吩并[2,3-C]吡喃-3-羧酸

Ki: 13 nM (Rab7)

CID-1067700 (ML282) is a pan GTPase inhibitor, and competitively inhibits Rab7 with a K _i of 13 nM. CID-1067700 shows inhibitory activity against nucleotide binding by Rab7, with K _d s of 100 nM and 40 nM for BODIPY-GTP and BODIPY-GDP, respectively. With increasing concentration, CID-1067700 causes strong inhibition on binding of the BODIPY-linked nucleotides, with EC ₅₀ values of 11.22 ± 1.34 nM for BODIPY-GTP and 20.96 ± 1.34 nM for BODIPY-GDP and calculated K _i values of 12.89 nM and 19.70 nM respectively. CID-1067700 (10 μM) has no effect on the rate of release of bound BODIPY-linked nucleotide by wild type Rab7 under equilibrium binding conditions. CID-1067700 (0-40 μM) inhibits Rab7 activity, NF-κB activation as well as AID induction in B cells. Furthermore, CID-1067700 binds Rab7 with a high affinity (EC ₅₀ : 10-20 nM), and blocks Class switch DNA recombination (CSR) in B cells via targeting Rab7.

CID-1067700 (ML282; 16 mg/kg, i.p.) prevents disease development in lupus-prone mice by Rab7 inhibition, and reduces IgG-IC deposition in MRL/ Fas ^lpr/lpr mice. CID-1067700 also targets B cells and specifically impairs the CSR machinery in vivo.