CID-1067700

CID-1067700 is a pan GTPase inhibitor, and competitively inhibits Ras-related in brain 7 (Rab7) with a Ki of 13 nM.

Signaling Pathways >> GPCR/G Protein >> Ras

Research Areas >> Inflammation/Immunology

Ki: 13 nM (Rab7)[1]

CID-1067700 is a pan GTPase inhibitor, and competitively inhibits Rab7 with a Ki of 13 nM. CID-1067700 shows inhibitory activity against nucleotide binding by Rab7, with Kds 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 EC50 values of 11.22 ± 1.34 nM for BODIPY-GTP and 20.96 ± 1.34 nM for BODIPY-GDP and calculated Ki 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[1]. 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 (EC50: 10-20 nM), and blocks Class switch DNA recombination (CSR) in B cells via targeting Rab7[2].

CID-1067700 (16 mg/kg, i.p.) prevents disease development in lupus-prone mice by Rab7 inhibition, and reduces IgG-IC deposition in MRL/Faslpr/lpr mice. CID-1067700 also targets B cells and specifically impairs the CSR machinery in vivo[2].

To treat human and mouse B cells in vitro with the Rab7 inhibitor, CID-1067700 is diluted in DMSO and added to cell cultures to the final concentration of 40 μM. CID-1067700 or DMSO is added either at the time when B cell stimulation started, or 66 h after B cells are stimulated with LPS plus IL-4, TGF-β, anti-δ/dex and RA, for analysis of plasma cell survival[2].

Mice[2] For in vivo treatment, CID-1067700 dissolved in DMSO (stock concentration 40 mM, 16 mg/mL) is diluted with the solvent to the final volume of 50 μL and injected intraperitoneally (i.p.) once per week at the dose of 16 mg/kg body weight. C57, MRL/Faslpr/lpr and C57/Sle1Sle2Sle3 mice injected i. p. with the vehicle DMSO (50 μL). For survival studies and skin lesion analyses, MRL/Faslpr/lpr mice are treated with nil or CID-1067700 for 10 weeks and maintained until moribund (e.g., showing signs of severe loss of mobility, hunched back, piloerection, ruffled fur, dyspnea, gasping and weight loss), at which point they are euthanized[2].

[1]. Agola JO, et al. A competitive nucleotide binding inhibitor: in vitro characterization of Rab7 GTPase inhibition. ACS Chem Biol. 2012 Jun 15;7(6):1095-108.

[2]. Lam T, et al. Small Molecule Inhibition of Rab7 Impairs B Cell Class Switching and Plasma Cell Survival To Dampen the Autoantibody Response in Murine Lupus. J Immunol. 2016 Nov 15;197(10):3792-3805.

ARS-853 | ARS-1620 | NSC 23766 | ML 141 | Salirasib | Pan-RAS-IN-1 | Rhosin hydrochloride | CASIN | EHT 1864 | EHop-016 | 1A-116 | CCG 1423 | K-Ras(G12C) inhibitor 12 | ZCL 278 | Y16