Description
GNF-2 is an allosteric inhibitor of Bcr-Abl (IC
50 = 267 nM). It is selective for Bcr-Abl over c-Abl and a panel of 63 additional kinases at 10 μM. It inhibits proliferation of Ba/F3 cells (IC
50 = 138 nM). GNF-2 (10 μM) reduces viral titers in Vero cells infected with infectious bronchitis virus (IBV), a coronavirus,
via inhibition of IBV surface glycoprotein-induced syncytia formation and virus-cell fusion. It inhibits LPS-induced production of nitric oxide (NO) and TNF-α in BV-2 microglia when used at concentrations of 10 and 20 μM. GNF-2 (1 and 10 mg/kg) reduces paw edema and increases the latency to paw withdrawal in a mouse model of inflammatory pain induced by complete Freund’s adjuvant (CFA). It also decreases mechanical and thermal hyperalgesia in a mouse model of diabetic neuropathy induced by streptozotocin (STZ; ).
Uses
Bcr-abl Inhibitor is an inhibitor of c-Abl and Bcr-abl activity. It is a COVID19-related research product.
Definition
ChEBI: 3-[6-[4-(trifluoromethoxy)anilino]-4-pyrimidinyl]benzamide is a member of pyrimidines.
General Description
A cell-permeable and reverisble pyrimidine compound that binds to the c-abl myristoyl binding pocket and acts as an allosteric, non-ATP-competitive inhibitor of cellular Bcr-abl activity and Bcr-abl-dependent cellular functions. Exhibits little inhibitory effect against a panel of 63 kinases even at concentration as high as 10 μM. Exhibits potent and selective antiproliferative activity toward Bcr-abl-expressing cells (IC
50 = 138 nM, 194 nM, 268 nM and 273 nM in Ba/F3.p210, Ba/F3.p
185Y253H, SUP-B15 and Ba/F3.p
210E255V, and K562, respectively). Brij-35 is reported to mask the inhibitory effect of GNF-2 in cell-free c-abl and Bcr-abl kinase assays.
Biochem/physiol Actions
GNF-2 belongs to a new class of Bcr-abl inhibitors. GNF-2 appears to bind to the myristoyl binding pocket, an allosteric site distant from the active site, stabilizing the inactive form of the kinase. It inhibits Bcr-abl phosphorylation with an IC50 of 267 nM, but does not inhibit a panel of 63 other kinases, including native c-Abl, and shows complete lack of toxicity towards cells not expressing Bcr-Abl. GNF-2 shows great potential for a new class of inhibitor to study Bcr-abl activity and to treat resistant Chronic myelogenous leukemia (CML), which is caused the Bcr-Abl oncoprotein.
