Zongertinib

Zongertinib is an inhibitor of mutant HER2 containing an activating exon 20 insertion (HER2YVMA. IC50 = 13 nM in a cellular phosphorylation assay using HEK cells). It is selective for the inhibition of HER2YVMA over wild-type EGFR (IC50 = 576 nM in a cellular phosphorylation assay using HEK cells). It is also selective for HER2 over 394 kinases in a kinase inhibition assay at 1 µM but does inhibit HER4 and BMX by >80% in the same assay at the same concentration. Zongertinib selectively inhibits the proliferation of Ba/F3 cells engineered to be dependent on HER2YVMA over those dependent on wild-type EGFR (IC50s = 16 and 1,549 nM, respectively). It also inhibits the proliferation of NCI H2170 non-small cell lung cancer (NSCLC) cells expressing wild-type HER2 or HER2YVMA (IC50s = 6. and 20 nM, respectively) but not A431 epidermal cancer cells dependent on EGFR (IC50 = >5,000 nM). Zongertinib (2.5-20 mg/kg twice per day) reduces tumor growth in an NCI N87 HER2-amplified gastric cancer mouse xenograft model. Formulations containing zongertinib have been used in the treatment of NSCLC in which tumor cells express HER2 activating mutations. Formal Name: N-[1-[8-[[3-methyl-4-[(1-methyl-1H-benzimidazol-5-yl)oxy]phenyl]amino]pyrimido[5,4-d]pyrimidin-2-yl]-4-piperidinyl]-2-propenamide. CAS Number: 2728667-27-2. Synonyms: BI 1810631. Molecular Formula: C29H29N9O2. Formula Weight: 535.6. Purity: >98%. Formulation (Request formulation change): A solid. Solubility: DMSO: Sparingly soluble: 1-10 mg/ml. SMILES: CC1=CC(NC2=NC=NC3=CN=C(N4CCC(NC(C=C)=O)CC4)N=C32)=CC=C1OC5=CC6=C(C=C5)N(C=N6)C. InChi Code: InChI=1S/C29H29N9O2/c1-4-26(39)34-19-9-11-38(12-10-19)29-30-15-23-27(36-29)28(32-16-31-23)35-20-5-8-25(18(2)13-20)40-21-6-7-24-22(14-21)33-17-37(24)3/h4-8,13-17,19H,1,9-12H2,2-3H3,(H,34,39)(H,31,32,35). InChi Key: YSGNGFPNTLERCR-UHFFFAOYSA-N. Storage: -20°C. Stability: > 4 years.