Table 3.
Representative small molecules targeting ATX in late-stage preclinical and clinical development.
| Compound(Company) | In vitro properties | Pre-clinical data | Clinical trials | ||||
|---|---|---|---|---|---|---|---|
| IC50(assay) | Mode of Binding (Ki)ATX inhibitor type(PDB structure entry) | ADMET | Pharmacokinetics | LPA inhibition | Disease targeting(Dose, route) | ||
|
GLPG-1690
Ziritaxestat (Galapagos) |
131 ± 12 nM (hATX, TOOS assay)1 418 nM (mouse plasma, 18:2 LPA, LC-MS/MS)1 542 nM (rat plasma, 18:2 LPA, LC-MS/MS)1 242 nM (human plasma, 18:2 LPA, LC-MS/MS)1 |
Competitive (15 nM, hATX), type IV inhibitor1 ( 5MHP ) |
hERG IC50: = 15 μM1
CYP3A4 TDI: negative1 |
iv clearance (L/h·kg): 0.23 (mouse), 0.69 (rat), 0.12 (dog)1 Cmax (mouse, 30 mg/kg per os): 21.367 μg/mL1 tmax (mouse, 30 mg/kg per os): 1 h1 t1/2 (mouse, 30 mg/kg per os): 3.8 h1 per os bioavailability (F%): 29 (mouse), 37 (rat), 63 (dog)1 |
95% (maximum) (30 mg/kg per os)1 |
Pulmonary fibrosis
(3, 10 or 30mg/kg per os)1 |
Phase I NCT03143712 NCT02179502 IPF Phase II NCT02738801 Phase III NCT03711162 NCT03733444 Scleroderma Phase II NCT03798366 NCT03976648 |
|
BLD-0409
Cudetaxestat (Blade Therapeutics) |
≤ 0.5 μM (LPC assay)2 |
– | – | – | – |
Metabolic disorders
(15mg/kg)2 |
Phase I NCT04146805 NCT04814472 NCT04814498 NCT04939467 |
|
ONO-8430506
(Ono Pharmaceuticals) |
5.1 nM (recomb. ATX, FS-3 assay)3 10.2 nM (hATX, LPC assay)3, 4 6.4 nM (mouse plasma, LPC assay)3 19 nM (rat plasma, LPC assay)3 5.5 nM (human plasma)3, 4 |
type II inhibitor | Protein plasma binding: rat (95.1%), human (99%)4
High selectivity to ATX3 |
iv clearance (mL min-1 kg-1): 8.2 (mouse), 4.7 (rat), 5.8 (dog)4
Vdss (L/kg): 1.5 (mouse), 1.9 (rat), 2.3 (dog)4 Cmax (1 mg/kg per os): 124 ng/mL (mouse), 261 ng/mL (rat), 1670 ng/mL (dog)4 t1/2 (1 mg/kg per os): 5.4 h (mouse), 2.5 h (rat), 5.9 h (dog)4 per os Bioavailability (F): 51.6% (rat), 71.1% (dog), 30.8% (monkey)4 |
96% (18:2 LPA, 3 mg/kg)3 93% (20:4 LPA, 3 mg/kg)3 >99% (18:2 & 20:4 LPA, 30 mg/kg)3 |
Prostatic hyperplasia
(0.3-10mg/kg, id)3 Breast cancer (10mg/kg, per os)5 Thyroid cancer (2mg/kg, per os)6 |
Preclinical evaluation |
|
PF-8380
(Pfizer) |
2.8 nM (hATX, FS-3 substrate)7 1.7 nM (hATX, LPC substrate)7 1.16 nM (mATX, FS-3 substrate)7 1.15 nM (fetal fibroblast cell line, LPC substrate)7 101 nM (human whole blood) |
Competitive (0.02-0.04 nM), type I inhibitor7 |
Solubility (pH = 6.8) = 0.011 mg/mL8
Poor solubility at physiological pH (7.4)8 IC50 hERG (cardiotoxicity) = 2.7 μM8 Permeability (PAMPA assay) = 81%8 |
rat iv clearance (mL min-1 kg-1) = 317
Vdss (L/kg) = 3.27 t1/2 = 1.2 h7 Cmax (10 mg/kg per os) = 2.55 μM7 tmax (10 mg/kg per os) = 0.67 h7 rat per os F (10 mg/kg) = 83%7 |
EC50 = 54.7 nM (16:0 LPA)7 EC50 = 84.6 nM (18:0 LPA)7 EC50 = 51.7 nM (20:0 LPA)7 |
Arthritis Hyperalgesia
(30mg/kg, po)7 Glioblastoma (10mg/kg, ip)9 Liver fibrosis (30mg/kg, ip)10 Lung allograft fibrosis (30mg/kg, per os)11 |
Preclinical evaluation |