Sunday, November 1, 2015

Drugs in Clinical Pipeline: ABT-494

ABT-494 [(3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide] is a second generation Jak kinase inhibitor with high selectivity for Jak1 (IC50 = 0.043 uM) thereby minimizing the potential for side effects related to Jak2 (IC50 = 0.2 uM) and Jak3 (IC50 = 2.3 uM) inhibition. ABT-494 is an ATP competitive inhibitor, and is most potent against Jak1 with concentration at 50% inhibition (IC50) of about 0.045 µM when tested at 0.1 mM ATP and less than 0.003 µM at 0.001 mM ATP [1].

Moreover, ABT-494 displays good selectivity in a panel of more than 60 protein kinases that also includes Jak3. Of the kinases in the panel, 14 kinases have an IC50 below 10 µM, but only 2 non-Jak kinases have IC50's below 1 µM (Rock1 at 0.55 µM and Rock2 at 0.43 µM).

ABT-494 was engineered for increased selectivity for Jak1 using structural predictions that indicated the potential for differential binding interactions outside the ATP-binding active site of Jak1 but not Jak2. The efficacy and selectivity of ABT-494 were tested in a battery of relevant cellular and in vivo pharmacology assays including bone marrow colony formation, adjuvant induced arthritis (AIA), erythropoietin induced reticulocyte deployment and NK/NKT cell suppression [2]. 

ABT-494 demonstrates approximately 74 fold selectivity for Jak1 over Jak2 in cellular assays dependent on specific, relevant cytokines. ABT-494 is a potent inhibitor of inflammation and bone loss in rat AIA and, compared to Tofacitinib, spares relevant essential physiological processes such as erythropoietin signaling and peripheral NK cell counts at similarly efficacious doses in rats. When dosed orally for 14 days in healthy human subjects ABT-494 did not decrease reticulocyte or NK cell counts at predicted efficacious doses consistent with its pharmacodynamic properties in rats.

The activity of ABT-494 is as follows:

IC50 (JAK1 enzyme assay) = 0.043 uM
IC50 (JAK2 enzyme assay) = 0.2 uM
IC50 (JAK3 enzyme assay) = 2.3 uM
IC50 (TYK2 enzyme assay) = 4.7 uM
IC50 (ROCK1 enzyme assay) = 0.55 uM

IC50 (ROCK2 enzyme assay) = 0.43 uM

Common Name: ABT-494
Synonyms: ABT-494; ABT494; ABT 494
IUPAC Name: (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide
CAS Number: 
Mechanism of Action: Kinase Inhibitor; Janus Kinase 1 Inhibitor
Indication: Anti-inflammatory Agents; Rheumatoid Arthritis Drug; Autoimmune Disease Treatment
Development Stage: Phase II

Company: AbbVie

1. Voss, J. W.; et. al. Jak1 selective inhibitor and uses thereof. WO2015061665A1
2. Voss, J.; et. al. THU0127 Pharmacodynamics of A Novel JAK1 Selective Inhibitor in Rat Arthritis and Anemia Models and in Healthy Human Subjects. Ann Rheum Dis 2014, 73, 222.