Zongertinib is a potent tyrosine kinase inhibitor. Zongertinib is used as an antineoplastic/anticancer agent. Zongertinib also works as a pHER2 and EGFR inhibitor and can inhibit a variety of cancers.
On August 8, 2025, the Food and Drug Administration granted accelerated approval to zongertinib (Hernexeos, Boehringer Ingelheim Pharmaceuticals, Inc.), a kinase inhibitor, for adults with unresectable or metastatic non-squamous non-small cell lung cancer (NSCLC) whose tumors have HER2 (ERBB2) tyrosine kinase domain (TKD) activating mutations, as detected by an FDA-approved test, and who have received prior systemic therapy. FDA also approved the Oncomine Dx Target Test (Life Technologies Corporation) as a companion diagnostic device to aid in detecting HER2 (ERBB2) TKD activating mutations in patients with non-squamous NSCLC who may be eligible for treatment with zongertinib.

Physicochemical Properties

Molecular Formula	C29H29N9O2
Molecular Weight	535.599664449692
Exact Mass	535.244
Elemental Analysis	C, 65.03; H, 5.46; N, 23.54; O, 5.97
CAS #	2728667-27-2
PubChem CID	160283094
Appearance	Light yellow to green yellow solid powder
LogP	4.1
Hydrogen Bond Donor Count	2
Hydrogen Bond Acceptor Count	9
Rotatable Bond Count	7
Heavy Atom Count	40
Complexity	870
Defined Atom Stereocenter Count	0
SMILES	C(NC1CCN(C2=NC=C3N=CN=C(NC4=CC=C(OC5=CC=C6N(C)C=NC6=C5)C(C)=C4)C3=N2)CC1)(=O)C=C
InChi Key	YSGNGFPNTLERCR-UHFFFAOYSA-N
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)
Chemical Name	N-[1-[4-[3-methyl-4-(1-methylbenzimidazol-5-yl)oxyanilino]pyrimido[5,4-d]pyrimidin-6-yl]piperidin-4-yl]prop-2-enamide
Synonyms	2728667-27-2; N-(1-(8-((3-methyl-4-((1-methyl-1H-benzo[d]imidazol-5-yl)oxy)phenyl)amino)pyrimido[5,4-d]pyrimidin-2-yl)piperidin-4-yl)acrylamide; N-(1-(8-((3-methyl-4-((1-methyl-1H-benzo(d)imidazol-5-yl)oxy)phenyl)amino)pyrimido(5,4-d)pyrimidin-2-yl)piperidin-4-yl)acrylamide; RefChem:823502; ...; Zongertinib;
HS Tariff Code	2934.99.9001
Storage	Powder-20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month
Shipping Condition	Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

Biological Activity

Targets	Human epidermal growth factor receptor 2 (HER2)
ln Vitro	Human epidermal growth factor receptor 2 (HER2) mutations have emerged as important oncogenic drivers in non-small cell lung cancer (NSCLC), leading to uncontrolled cell growth and survival. Zongertinib is an irreversible tyrosine kinase inhibitor of HER2. Its acrylamide moiety forms a covalent bond with the cysteine 805 residue of the HER2 receptor, thereby inhibiting HER2 phosphorylation and the activation of downstream signaling pathways, including extracellular signal-regulated kinase (ERK), mitogen-activated protein kinases (MAPK), and PI3K/Akt. The inhibition of these pathways leads to a reduction in the proliferation of lung cancer cells harboring HER2 tyrosine kinase domain activating mutations.
ln Vivo	In vivo, zongertinib demonstrated anti-tumor activity in mouse xenograft models of NSCLC with HER2 tyrosine kinase domain activating mutations. A key characteristic of zongertinib is its selectivity for HER2 - including exon 20 insertion mutations - while sparing wild-type epidermal growth factor receptor (EGFR), which is believed to limit EGFR-associated toxicities. In a preclinical proliferation assay, zongertinib showed 100-fold greater sparing activity for wild-type EGFR compared to its activity against the HER2 YVMA mutation. It is effective against various HER2 tyrosine kinase domain mutations, including A775-G776YVMA and P780-Y781insGSP. Zongertinib has also demonstrated intracranial activity, with an intracranial objective response rate of 37% and a disease control rate of 83% observed in patients with baseline brain metastases in a subanalysis of the Beamion LUNG-1 trial.
ADME/Pharmacokinetics	Absorption The absolute oral bioavailability of zongertinib is 76.2%. Following oral administration in patients with solid tumors, the median time to maximum plasma concentration (Tmax) for zongertinib is approximately 2 hours. At the recommended dose of 120 mg once daily, the steady-state geometric mean maximum concentration (Cmax,ss) is 3.0 µmol/L and the total systemic exposure (AUC) is 34 µmol.h/L. Zongertinib exposure increases in an approximately dose-proportional manner over a range of 60 mg to 360 mg. Accumulation is approximately 1.5-fold for AUC and 1.3-fold for Cmax, with steady state achieved within 2.5 days. Route of Elimination Zongertinib and its metabolites are eliminated primarily through the feces. Following a single oral radiolabeled dose in healthy participants, approximately 93% of the total dose was recovered in feces and 1.3% was recovered in urine. Of the administered dose, 31% was excreted as unchanged zongertinib in the feces, while only 0.2% was excreted as unchanged drug in the urine. Volume of Distribution The apparent oral volume of distribution of zongertinib in patients is 118 L. In a study in healthy volunteers, the volume of distribution at steady state following an intravenous microtracer dose was 138 L. Clearance In patients, the apparent oral clearance of zongertinib is 115 mL/min. A study in healthy volunteers using an intravenous microtracer dose determined the total plasma clearance to be 106 mL/min. Protein Binding Zongertinib is >99% protein-bound in plasma. The specific proteins to which it binds are unclear. Metabolism / Metabolites Zongertinib is primarily metabolized in the liver via three main pathways: CYP-mediated oxidation (48% to 62%), glucuronidation (13% to 25%), and glutathione conjugation (13% to 26%). The primary enzymes involved are CYP3A4 and CYP3A5 for oxidation and UGT1A4 for glucuronidation. In a human ADME study, 14 metabolites were identified - the two most abundant circulating metabolites were M551(1) (mono-oxidation) and M656(1) (cysteine conjugate), representing 5.7% and 2.5% of total plasma radioactivity, respectively. Biological Half-Life The effective half-life of zongertinib at steady state in patients is 12 hours. A single-dose study in healthy volunteers reported a longer terminal half-life of 42.7 hours after an intravenous dose and 45.2 hours after an oral dose.
Toxicity/Toxicokinetics	Efficacy was evaluated in patients with unresectable or metastatic, non-squamous NSCLC with HER2 (ERBB2) TKD mutations who had received prior systemic therapy and received zongertinib in Beamion LUNG-1 (NCT04886804), an open-label, multi-center, multi-cohort trial. The major efficacy outcome measures were objective response rate (ORR) and duration of response (DOR) determined by blinded independent central review per RECIST v1.1. Among 71 patients who received prior platinum-based chemotherapy but had not been previously treated with a HER2-targeted tyrosine kinase inhibitor or antibody-drug conjugate (ADC), ORR was 75% (95% CI: 63, 83), with 58% having a DOR ≥ 6 months. Among 34 patients previously treated with platinum-based chemotherapy and a HER2-targeted ADC, ORR was 44% (95% CI: 29, 61), with 27% having a DOR ≥ 6 months. The prescribing information includes warnings and precautions for hepatotoxicity, left ventricular dysfunction, interstitial lung disease/pneumonitis, and embryo-fetal toxicity. The recommended zongertinib dose is based on body weight. For patients weighing < 90 kg, the dose is 120 mg orally once daily. For patients weighing ≥ 90 kg, the dose is 180 mg orally once daily. Zongertinib may be taken with or without food and continued until disease progression or unacceptable toxicity. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-zongertinib-non-squamous-nsclc-her2-tkd-activating-mutations
References	[1]. WHO Drug Informat ion - World Health Organization (WHO). [2]. Synthesis of diazino-pyrimidines as anticancer agents: World Intellectual Property Organization, WO2021213800. 2021-10-28. [3]. Emerging Targeted Therapies in Advanced Non-Small-Cell Lung Cancer. Cancers (Basel). 2023 May 24;15(11):2899.
Additional Infomation	Zongertinib is a selective, irreversible tyrosine kinase inhibitor that targets human epidermal growth factor receptor 2 (HER2). It covalently binds to the HER2 receptor, including exon 20 insertions, and inhibits downstream signaling pathways while sparing wild-type epidermal growth factor receptor (EGFR), which serves to limit associated toxicities. On August 8, 2025, the US FDA granted accelerated approval to zongertinib for the treatment of advanced forms of non-small cell lung cancer (NSCLC) with HER2 tyrosine kinase domain activating mutations. Zongertinib is a Kinase Inhibitor. The mechanism of action of zongertinib is as a HER2/Neu/cerbB2 Antagonist, and Breast Cancer Resistance Protein Inhibitor. Zongertinib is an orally bioavailable inhibitor of the receptor tyrosine kinase human epidermal growth factor receptor 2 (HER2; ErbB2; HER-2), with potential antineoplastic activity. Upon oral administration, zongertinib covalently binds to and inhibits the activity of both wild-type and HER2 mutants, including HER2 mutants with exon 20 insertion (ex20ins) mutations. This prevents HER2-mediated signaling and may lead to cell death in HER2-expressing tumor cells. HER2, a receptor tyrosine kinase overexpressed on a variety of tumor cell types, plays an important role in tumor cell proliferation and tumor vascularization. ZONGERTINIB is a small molecule drug with a maximum clinical trial phase of III and has 1 investigational indication. Zongertinib is indicated for the treatment of adult patients with unresectable or metastatic non-squamous non-small cell lung cancer (NSCLC) whose tumors have HER2 (ERBB2) tyrosine kinase domain activating mutations and who have received prior systemic therapy.

Solubility Data

Solubility (In Vitro)

DMSO: 31.25 mg/mL (58.35 mM)

Solubility (In Vivo)

Solubility in Formulation 1: ≥ 2.5 mg/mL (4.67 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly. Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.  (Please use freshly prepared in vivo formulations for optimal results.)

Preparing Stock Solutions		1 mg	5 mg	10 mg
	1 mM	1.8671 mL	9.3353 mL	18.6706 mL
	5 mM	0.3734 mL	1.8671 mL	3.7341 mL
	10 mM	0.1867 mL	0.9335 mL	1.8671 mL

*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.