DHODH-IN-22

DHODH-IN-22 is a potent, selective and orally active dihydroorotate dehydrogenase (DHODH) inhibitor with an IC50 value of 0.3 nM. DHODH-IN-22 can be used for researching acute myelogenous leukemia (AML)[1].

Research Areas >> Cancer

IC50: 0.3 nM (human DHODH), 10 nM (mouse DHODH), 130 nM (rat DHODH), 4.2 nM (dog DHODH), 0.54 nM (monkey DHODH)[1]

DHODH-IN-22 (compound 29) exhibits antiproliferative activity against MOLM-13 and THP-1 cells[1]. Cell Proliferation Assay[1] Cell Line: MOLM-13 and THP-1 Concentration: 0-30 nM Incubation Time: 72 h Result: Exhibited antiproliferative activity against MOLM-13 and THP-1 cells with IC50s of 0.4 nM and 1.4 nM, respectively.

DHODH-IN-22 (1.9-7.5 mg/kg; PO; QD for 5 days) significantly inhibits MOLM-13 tumor growth in mice, and exhibits no significant impact on body weight[1]. DHODH-IN-22 (2 mg/kg for IV and 10 mg/kg for PO; single dosage) has favorable pharmacokinetic property[1]. Pharmacokinetic Parameters of DHODH-IN-22 (compound 29) in mouse and rat[1]. Mouse IV 2 mg/kg and PO 10 mg/kg Rat IV 2 mg/kg and PO 10 mg/kg CL (mL/min/kg) 7.3 7.6 Vdss (L/kg) 2.4 2.2 t1/2 (ng/mL) 5 4 Cmax (ng/mL) 3810 2193 tmax (h) 1.0 4.0 AUC0-inf (ng/mL·h) 23046 23807 F (%) 110 106 Animal Model: Female NSG mice (implanted subcutaneously with 2 × 106 MOLM-13 tumor cells)[1] Dosage: 1.9, 3.75 and 7.5 mg/kg Administration: PO; QD for 5 days Result: Significantly inhibited tumor growth with ΔTGI% of 71, 76, and 79% at 1.9, 3.75 and 7.5 mg/kg, respectively, and exhibited no significant impact on body weight over the course of 5 days. Animal Model: Rat and mouse[1] Dosage: 2 mg/kg IV and 10 mg/kg PO Administration: IV or PO; single dosage (Pharmacokinetic analysis) Result: Exhibited low clearance and high oral bioavailability in both species.

[1]. Cisar JS, et al. N-Heterocyclic 3-Pyridyl Carboxamide Inhibitors of DHODH for the Treatment of Acute Myelogenous Leukemia. J Med Chem. 2022 Aug 4.