Kinase selectivity and secondary pharmacology profile
| Kinases Tested for IC50 | IC50 Values (compound, nM) | Repeats (n) | ||||||
|---|---|---|---|---|---|---|---|---|
| TGFβR1 (ALK5) | 0.8 (0.2–4.2)a | 3 | ||||||
| ACVR1B (ALK4) | 3.14b | 1 | ||||||
| MAP4K4 (HGK) | 4.49 | 1 | ||||||
| CEREP Secondary Pharmacology Screen | Primary Profiling | Follow-up Profiling | ||||||
| Target with 50% Response in Primary Assay | Assay Format | Test Concentration (μM) | % Inhibition at Test Concentration | Endpoint | Endpoint Value (nM) | Exposure Multiplesb | ||
| GABAA Cl Ch (BZD site) | Binding | 10 | 61 | Ki | 730 | 16.6x | ||
| PDE4D2 | Enzymatic | 10 | 76 | IC50 | 340 | 7.7x | ||
| P38α MAPK | Enzymatic | 10 | 66 | IC50 | 610 | 13.9x | ||
| VEGFR2 kinase | Enzymatic | 10 | 96 | IC50 | 897 | 20.4x | ||
ACVR1B, activin A receptor type-IB; BZD, benzodiazepine; GABA ClCh, γ-aminobutyric acid chloride channel; MAPK, mitogen-activated protein kinase; PDE4D2, phosphodiesterase 4D2; VEGFR, vascular endothelial growth factor receptor.
↵a 95% geometric confidence interval of 0.2 to 4.2 nM (n = 3) as measured in a LanthaScreen competition binding assay using a recombinant catalytic kinase domain and ATP site targeted fluorescent tracer.
↵b Exposure multiple relative to the predicted unbound Cmax (44.3 nM) at the projected clinically efficacious dose of 225 mg twice a day, based on efficacious exposure in MC38 nonclinical tumor model.