Description
AMG 925 is a dual inhibitor of FMS-related tyrosine kinase 3 (FLT3) and cyclin-dependent kinase 4 (Cdk4; IC50s = 1 and 3 nM, respectively). It is selective for FLT3 and Cdk4 over Cdk1 (IC50 = 2.22 μM). AMG 925 also binds to FLT3ITD, FLT3D835Y, FLT3D835H, FLT3K663Q, and FLT3N841I (Kds = 1-4 nM). It inhibits proliferation of MOLM-13, COLO 205, and U937 cancer cells (IC50s = 19, 55, and 52 nM, respectively). AMG 925 (50, 75, and 150 mg/kg) reduces intratumor levels of pSTAT5 and pRb and inhibits tumor growth in a MOLM-13 acute myeloid leukemia (AML) mouse xenograft model.
Uses
AMG 925 is a FLT3 and CDK4 Dual Kinase Inhibitor with Preferential Affinity for the Activated State of FLT3.
Definition
ChEBI: AMG-925 is an organic heterotricyclic compound that is 9H-pyrido[4',3':4,5]pyrrolo[2,3-d]pyrimidine which is substituted by a [6-(hydroxyacetyl)-5,6,7,8-tetrahydro-1,6-naphthyridin-2-yl]nitrilo group at position 2 and by a trans-4-methylcyclohexyl group at position 9. It is a FLT3 and CDK4 dual kinase inhibitor that has antineoplastic activity. Currently under clinical investigation in patients with relapsed or refractory acute myeloid leukemia (AML). It has a role as an antineoplastic agent, an apoptosis inducer, an EC 2.7.11.22 (cyclin-dependent kinase) inhibitor and an EC 2.7.10.1 (receptor protein-tyrosine kinase) inhibitor. It is a secondary amino compound, a tertiary amino compound, a naphthyridine derivative, a primary alpha-hydroxy ketone and an organic heterotricyclic compound.
in vivo
MOLM13 tumor-bearing mice are dosed twice daily by oral administration 6 hours apart with 12.5, 25, or 37.5 mg/kg AMG 925. Tumors are then harvested 3, 9, 12, and 24 hours after the first dose, and analyzed for levels of P-STAT5 and P-RB. Maximum inhibition of P-STAT5 and P-RB is achieved at 6 and 12 hours respectively at the 37.5 mg/kg dose of AMG 925. Interestingly, a rebound of P-STAT5 at 24 hours is observed, possibly as a result of compensational feedback. The pharmacodynamic responses of P-STAT5 and P-RB inhibition correlated with plasma concentrations of AMG 925. AMG 925 inhibits AML xenograft tumor growth by 96% to 99% without significant body weight loss. The antitumor activity of AMG 925 correlates with the inhibition of STAT5 and retinoblastoma protein (RB) phosphorylation, the pharmacodynamic markers for inhibition of FLT3 and CDK4, respectively. In addition, AMG 925 is also found to inhibit FLT3 mutants (e.g., D835Y) that are resistant to the current FLT3 inhibitors (e.g., AC220 and Sorafenib)[1].
IC 50
FLT3: 2 nM (IC50); CDK4: 3 nM (IC50); CDK6: 8 nM (IC50); CDK2: 375 nM (IC50); CDK1: 1.9 μM (IC50)
References
[1] keegan k, li c, li z, ma j, ragains m, coberly s, hollenback d, eksterowicz j, liang l, weidner m, huard j, wang x, alba g, orf j, lo mc, zhao s, ngo r, chen a, liu l, carlson t, quéva c, mcgee lr, medina j, kamb a, wickramasinghe d, dai k. preclinical evaluation of amg 925, a flt3/cdk4 dual kinase inhibitor for treating acute myeloid leukemia. mol cancer ther. 2014 apr;13(4):880-9.
