IRAK4-IN-14

IRAK4-IN-14 (compound 28) is a potent, selective and orally active IRAK4 inhibitor with an IC50 of 0.003 µM. IRAK4-IN-14 shows good PK parameters in rats and mouse. IRAK4-IN-14 shows synergistic in vitro activity against MyD88/CD79 double mutant ABC-DLBCL in combination with Acalabrutinib[1].

Research Areas >> Cancer

Signaling Pathways >> Immunology/Inflammation >> IRAK

Signaling Pathways >> Protein Tyrosine Kinase/RTK >> IRAK

IRAK4:0.003 μM (IC50)

IRAK4-IN-14 (compound 28) shows cell pIRAK4 potencies with an IC50 of 0.11 µM[1]. IRAK4-IN-14 (compound 28) shows selectivity with IC50s of 0.003,1.4, >8, >9, 0.053, 0.27, 0.76, 0.27 µM for IRAK4, IRAK1, BTK, Flt3, PI3Kδ, TRKa, TRKb, TRKc, respectively[1].

IRAK4-IN-14 (i.v. or p.o.) shows good PK parameters with oral bioavailability of 66% for mouse[1]. Pharmacokinetic Parameters of IRAK4-IN-14 in Male Han Wistar rats, male CD1 mice, male Cynomolgus monkeys[1]. parameter Value A2B Papp 31 Efflux ratio 1.4 Solubility (µM) 800 Rat/mouse/monkey/human %free 21/16/33/21 Rat LM/H CLint 16/5.6 Mouse LM/H CLint 13/11 Minipig LM/H CLint 18/8.2 Dog LM/H CLint 21/4.5 Monkey LM/H CLint 35/4.7 Rat CL 15 Vdss 4.3 t1/2 5.2 F% 55% Mouse CL 17 Vdss 4.1 t1/2 4.2 F% 66% Monkey CL 68 Vdss 8.6 t1/2 1.4Male Han Wistar rats; 1 mg/kg i.v.; 2 mg/kg p.o.; Male CD1 mice; 0.5 mg/kg i.v.; 1 mg/kg p.o.; Male Cynomolgus monkeys; 1 mg/kg i.v.[1].

[1]. Degorce SL, et al. Improving metabolic stability and removing aldehyde oxidase liability in a 5-azaquinazoline series of IRAK4 inhibitors. Bioorg Med Chem. 2020 Dec 1;28(23):115815.