JBJ-09-063 hydrochloride

JBJ-09-063 hydrochloride is a mutant-selective allosteric EGFR inhibitor with IC50s of 0.147 nM, 0.063 nM, 0.083 nM and 0.396 nM for EGFR L858R, EGFR L858R/T790M, EGFR L858R/T790M/C797S and EGFRLT/L747S. JBJ-09-063 hydrochloride effectively reduces EGFR, Akt and ERK1/2 phosphorylation. JBJ-09-063 hydrochloride is effective across EGFR tyrosine kinase inhibitor (TKI)-sensitive and resistant models. JBJ-09-063 hydrochloride can be used for researching EGFR-mutant lung cancer[1].

JBJ-09-063 is remarkably effective at inhibiting cell growth and leads to a significant increase in apoptosis, even though H3255GR cells are resistant to gefitinib as a single agent, as they contain an EGFR T790M mutation[1].

JBJ-09-063 is effective in H1975 cells exogenously expressing the osimertinib-resistant mutations[1].

JBJ-09-063 exhibits IC50s of 50 nM and 6 nM in Ba/F3 cell when use alone or combination with Cetuximab [2].

JBJ-09-063 (3 mg/kg i.v., 20 mg/kg p.o.) exhibits favorable pharmacokinetics properties and is sufficiently stable to deliver good efficacy upon oral dosing[2].

Animal Model: Mice[2]

Dosage: 3 mg/kg for i.v., 20 mg/kg for p.o.

Administration: i.v. and p.o.; single dosage

Result: Pharmacokinetic Parameters of JBJ-09-063 in mice[2].

Cl (mL/min/kg), i.v. T1/2 (h) Vss (L/kg) F (%) AUC 8h (ng.h/mL)

15.7 2.3 2.5 15 2398

References:
[1]. To C, et al. An allosteric inhibitor against the therapy-resistant mutant forms of EGFR in non-small cell lung cancer. Nat Cancer. 2022 Apr;3(4):402-417.
[2]. Gero TW, Scott DA, et al. Quinazolinones as allosteric fourth-generation EGFR inhibitors for the treatment of NSCLC. Bioorg Med Chem Lett. 2022 Jul 15;68:128718.