BI-4142

BI-4142 is a potent, highly selective and orally active HER2 inhibitor with an IC50 of 5 nM[1].

Research Areas >> Cancer

Signaling Pathways >> JAK/STAT Signaling >> EGFR

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

HER2:5 nM (IC50)

BI-4142 shows inhibition with IC50 values of 10 nM, 18 nM, 270 nM and 2400 nM against HEK HER2YVMA, Ba/F3 HER2YVMA, HEK EGFRWT and Ba/F3 EGFRWT, respectively[1]. BI-4142 (1 nM-5 μM, 72 h or 96 h) shows antiproliferative activity against tumor cells[1]. BI-4142 displays good permeability and no PgP-mediated efflux liability in the CaCo-2 assay[1]. BI-4142 inhibits HER2-dependent cell lines and inhibits downstream signaling[1]. Cell Proliferation Assay[1] Cell Line: NCI-H2170 HER2WT, NCI-H2170 HER2YVMA, A431 EGFRWT, Ba/F3 HER2YVMA, Ba/F3 HER2YVMA,S783C, Ba/F3 EGFRWT and Ba/F3 EGFRC775S cells Concentration: 1 nM-5 μM Incubation Time: 72 h or 96 h Result: Showed antiproliferative effect with IC50 values of 16 nM, 82 nM, >5 µM, 4 nM, 24 nM, 718 nM and 43 nM against NCI-H2170 HER2WT, NCI-H2170 HER2YVMA, A431 EGFRWT, Ba/F3 HER2YVMA, Ba/F3 HER2YVMA,S783C, Ba/F3 EGFRWT and Ba/F3 EGFRC775S, respectively.

BI-4142 (0-100 mg/kg; p.o.; twice per day for 40 days) inhibits tumor growth and inhibits oncogenic signaling[1]. Animal Model: NMRI-Foxn1nu mice, PC-9 HER2YVMA xenograft model[1] Dosage: 3, 10, 30 and 100 mg/kg Administration: Oral administration, twice per day for 40 days Result: Resulted in tumor regressions in a dose-dependent manner (113%, 126%, 153% and 166% tumor growth inhibition at 3, 10, 30 and 100 mg/kg, respectively). Animal Model: BomTac:NMRI Foxn1nu mice[1] Dosage: 1 mg/kg or 10mg/kg and 100 mg/kg Administration: IV for 1 mg/kg, PO for 10mg/kg and 100 mg/kg (Pharmacokinetic Analysis) Result: In vivo mouse PK data for BI-4142[1] Compound Dose iv/po (mg/kg) tmax (h) Cmax (nM) AUD (h•nM) Plasma CL (mL/min/kg) % F i.v., 1mg/kg n/a n/a 3,280 9.69 n/a BI-4142 p.o., 10 mg/kg 0.83 8,600 23,200 n/a 71 p.o., 100 mg/kg 0.67 36,400 196,000 n/a 60

[1]. Wilding B, 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.