Description
NSC-23766 (733767-34-5) is a selective inhibitor of Rac1-GEF interaction. Prevents Rac1 activation by Rac-specific guanine nucleotide exchange factors (GEFs) Trio and Tiam1 (IC50 ca. 50 μM) with no effect on the closely related Cdc42 or RhoA. In cells, it blocks serum or PDGF-induced Rac-1 activation and lamellipodia formation. NSC-23766 suppressed the growth of wild-type NIH 3T3 cells but was inactive in cells expressing the constitutively active Rac1 mutant, L61Rac1.1 It is a useful tool to probe the involvement of Rac1 in cell signalling.2 Off target effect: antagonist at muscarinic acetylcholine receptors.3 Cell permeable.
Uses
The compound blocks activation by the guanine nucleotide exchange factors Trio and Tiam1, but does not affect interactions with RhoA or Cdc42. NSC23766 blocks ADP-mediated platelet aggregation. Inhibition of Rac1 by NSC23766 restores sensitivity to trastuzumab by restoring down-regulation of ErbB2. Membrane type 1-matrix metalloproteinases (MT-1MMP) expression in CB CD34+ cells has been reported to decrease in the presence of NSC 23766. Silveta compress investigations indicate that NSC 23766 depolarizes endomembrane cycling, altered polar adhesive secretion, and tip growth.
Definition
ChEBI: NSC 23766 is an aminopyrimidine that is 6-methylpyrimidine-2,4-diamine in which the amino groups at positions 2 and 4 are substituted by 5-(diethylamino)pentan-2-yl and 4-amino-2-methylquinolin-6-yl groups respectively. An inhibitor of the signalling G-protein known as RAC1 (Ras-related C3 botulinum toxin substrate 1). It has a role as an EC 3.6.5.2 (small monomeric GTPase) inhibitor, an antiviral agent, a muscarinic antagonist and an apoptosis inducer. It is an aminoquinoline, an aminopyrimidine, a primary amino compound, a secondary amino compound and a tertiary amino compound.
Biological Activity
Selective inhibitor of Rac1-GEF interaction. Prevents Rac1 activation by Rac-specific guanine nucleotide exchange factors (GEFs) TrioN and Tiam1 (IC 50 ~ 50 μ M) without affecting Cdc42 or RhoA activation. Inhibits Rac1-mediated cell functions and reported to reverse tumor cell phenotyes in prostate cancer cells.
in vivo
NSC23766 (2.5 mg/kg/day, i.p.) significantly attenuates the onset of spontaneous diabetes in NOD mice, without significant effects on the growth (body weights) of the mice. NSC23766 significantly increases the expression of Rac1 and CHOP, a marker for ER-stress, in islets from NOD mice[1].
References
[1] YUAN GAO. Rational design and characterization of a Rac GTPase-specific small molecule inhibitor.[J]. Proceedings of the National Academy of Sciences of the United States of America, 2004, 101 20: 7618-7623. DOI:
10.1073/pnas.0307512101[2] JAY SHANKAR. Raft endocytosis of AMF regulates mitochondrial dynamics through Rac1 signaling and the Gp78 ubiquitin ligase.[J]. Journal of cell science, 2013: 3295-3304. DOI:
10.1242/jcs.120162[3] MAGDOLNA LEVAY. NSC23766, a widely used inhibitor of Rac1 activation, additionally acts as a competitive antagonist at muscarinic acetylcholine receptors.[J]. Journal of Pharmacology and Experimental Therapeutics, 2013, 347 1: 69-79. DOI:
10.1124/jpet.113.207266
