BI-1622

BI-1622 is an orally active, potent and highly selective HER2 (ERBB2) inhibitor, with an IC50 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 drug metabolism and pharmacokinetics profile[1].

Research Areas >> Cancer

Signaling Pathways >> JAK/STAT Signaling >> EGFR

Signaling Pathways >> JAK/STAT Signaling >> JAK

Signaling Pathways >> Epigenetics >> JAK

Signaling Pathways >> Stem Cell/Wnt >> JAK

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

Signaling Pathways >> PI3K/Akt/mTOR >> PI4K

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

Signaling Pathways >> Cell Cycle/DNA Damage >> CDK

Signaling Pathways >> MAPK/ERK Pathway >> Raf

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

HER2:7 nM (IC50)

ErbB4

EGFR

CDK11B

JAK3

BI-1622 (0-5 µM, 72 h or 96 h) inhibits the proliferation of HER2-dependent cell lines[1]. 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[1]. BI-1622 displays good permeability and no PgP-mediated efflux liability[1]. BI-1622 shows good in vitro clearance in mouse liver microsomes and mouse hepatocytes[1]. Cell Proliferation Assay[1] Cell 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 IC50 values below 50 nM in tumor cell lines, while sparing EGFRWT-driven cells.

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[1]. BI-1622 (0-100 mg/kg, orally, twice daily) inhibits tumor growth and inhibits oncogenic signaling in vivo[1]. 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)[1] 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)[1] 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%.

[1]. Lamarre L, et al. Discovery of potent and selective HER2 inhibitors with efficacy against HER2 exon 20 insertion-driven tumors, which preserve wild-type EGFR signaling. Nat Cancer. 2022 Jul;3(7):821-836.