Neurotinib (NCATS-SM1976) is a potent, selective c-Abl allosteric inhibitor, reduces c-Abl phosphorylation and the activation of CRKII, shows potential to prevent epileptic-like seizure.
Neurotinib binds c-Abl more strongly than GNF2, binds to c-Abl myristoyl pocket, the same as GNF2.
Neurotinib inhibits CRKII-GST phosphorylation in the 0.1-1 μM concentration range in an in vitro phosphorylation assay incubating CRKII (a c-Abl cellular target).
Neurotinib inhibits cell proliferation of K562 cells with IC50 of 2 uM, which depends on BCR-ABL activity.
Neurotinib reduces c-Abl phosphorylation and the activation of CRKII, exerts a protective effect against 100 μM NMDA toxicity in neurons at 1 uM.
Neurotinib displays improved selectivity and CNS pharmacokinetics in comparison to other c-Abl inhibitors.
Neurotinib (5 mg/kg) for 3 days inhibits the increase in c-Abl phosphorylation in pilocarpine-induced SE mice, protecting mice against seizures and improving survival.
Neurotinib ameliorates the convulsive state in kainic-acid-induced SE mice.
Neurotinib has been shown to be effective in Niemann-Pick A (NPA) and Alzheimer's mice models.