BI-1622 is an orally active, potent and highly selective HER2 ( ERBB2 ) inhibitor, with an IC 50 of 7 nM. BI-1622 shows greater than 25-fold selectivity over EGFR . BI-1622 shows high antitumor efficacy in vivo in xenograft mouse tumor models with engineered H2170 and PC9 cells and had a favorable agent metabolism and pharmacokinetics profile
In Vitro
BI-1622 (0-5 µM, 72 h or 96 h) inhibits the proliferation of HER2-dependent cell lines. BI-1622 induces a dose-dependent decrease in pHER2 and pERK levels in NCI-H2170 HER2YVMA and PC-9 HER2YVMA cells with an accompanying decrease in DUSP6 messenger RNA levels. BI-1622 displays good permeability and no PgP-mediated efflux liability. BI-1622 shows good in vitro clearance in mouse liver microsomes and mouse hepatocytes. MCE has not independently confirmed the accuracy of these methods. They are for reference only. Cell Proliferation AssayCell Line: Ba/F3 cells Concentration: 0-5 µM Incubation Time: 72 h or 96 h Result: Potently inhibited the proliferation of cancer cell lines dependent on amplified HER2 or an NRG-1 fusion. Inhibited different HER2 oncogenic variants and HER2WT with IC 50 values below 50 nM in tumor cell lines, while sparing EGFRWT-driven cells.
In Vivo
BI-1622 (1 mg/kg, IV; 10 and 100 mg/kg, Orally; once) shows moderate clearance, a moderate volume of distribution, and good to moderate bioavailability . BI-1622 (0-100 mg/kg, orally, twice daily) inhibits tumor growth and inhibits oncogenic signaling in vivo . MCE has not independently confirmed the accuracy of these methods. They are for reference only. Animal Model: Female NMRI-Foxn1nu mice (6-8 weeks old, 8-10 mice per cage, engrafted subcutaneously with PC-9 HER2YVMA, NCI-H2170 HER2YVMA or NCI-N87 cells) Dosage: 10, 30 and 100 mg/kg Administration: orally, twice daily Result: In the NCI-H2170 HER2YVMA mechanistic model, 100 mg/kg twice daily BI-1622 resulted in a delay in tumor growth (73% TGI). In the ST3107 HER2 exon 20 mutant model, both BI-4142 (100 mg/kg twice daily) resulted in tumor regressions. Animal Model: NMRI Foxn1nu mice (n=3 per group) Dosage: 1 mg/kg (IV); 10 and 100 mg/kg (Orally) Administration: IV, Orally; once (Pharmacokinetic Analysis) Result: Showed moderate in vivo clearance (50% hepatic blood flow), a moderate volume of distribution, and good to moderate bioavailability of up to 68%.
