Human epidermal growth factor receptor 2 (HER2)
Zongertinib targets HER2 (human epidermal growth factor receptor 2) and EGFR. It is a HER2-selective tyrosine kinase inhibitor that covalently binds to the HER2 tyrosine kinase domain, including both wild-type and mutated forms. Importantly, it spares EGFR signaling, which is a key feature that may reduce EGFR-related toxicities. Its mechanism of action involves irreversible inhibition of HER2-driven oncogenic signaling.

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.

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In vitro, Zongertinib potently and selectively blocks HER2, while sparing EGFR. It inhibits the growth of cells dependent on HER2 oncogenic driver events, including HER2-dependent human cancer cells resistant to trastuzumab deruxtecan. This demonstrates its efficacy in models of HER2-driven cancers, including those with acquired resistance to other therapies.

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.

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In vivo, Zongertinib has shown antitumor activity with inhibitory effects on pHER2 and EGF. It has translated into tumor regressions in genome-engineered models. Its oral bioavailability and potent activity support its evaluation in clinical settings for the treatment of HER2 aberration-positive solid tumors.

Cell-free assays for Zongertinib typically involve measuring its inhibitory activity against HER2 and EGFR kinases using biochemical kinase assays. The compound's IC50 values are determined by measuring the phosphorylation of a substrate in the presence of varying concentrations of the inhibitor. These assays are used to characterize the compound's potency and selectivity profile against HER2 and EGFR.

In vitro cellular assays are conducted to evaluate the functional activity of Zongertinib. HER2-dependent cancer cell lines are treated with the compound. Cell viability and proliferation are measured to assess the compound's anti-proliferative effects. HER2 phosphorylation and downstream signaling events are also measured to confirm inhibition of the target kinase.

In vivo animal experiments typically involve xenograft models of HER2-driven cancers. Mice bearing these tumors are administered Zongertinib orally. Tumor growth is monitored over time to assess the compound's efficacy. These studies are essential for demonstrating the in vivo antitumor activity of the compound.

Absorption
The absolute oral bioavailability of zogatinib is 76.2%. In patients with solid tumors, the median time to reach maximum plasma concentration (Tmax) after oral administration is approximately 2 hours. The recommended dose is 120 mg once daily, with a steady-state geometric mean maximum concentration (Cmax, ss) of 3.0 µmol/L and a total systemic exposure (AUC) of 34 µmol·h/L. Within the dose range of 60 mg to 360 mg, zogatinib exposure increases approximately dose-proportional. The cumulative AUC is approximately 1.5-fold, and the cumulative Cmax is approximately 1.3-fold, reaching steady state within 2.5 days.
Elimination Routes
Zogatinib and its metabolites are primarily excreted in feces. In healthy subjects, approximately 93% of the total dose is recovered in feces and 1.3% in urine after a single oral administration of the radiolabeled drug. Of the administered dose, 31% is excreted unchanged in feces, while only 0.2% is excreted unchanged in urine.
Volume of Distribution
The apparent oral volume of distribution of zongertinib in patients is 118 L. In a study of healthy volunteers, the steady-state volume of distribution was 138 L after intravenous administration of a microtracer.
Clearance
The apparent oral clearance of zongertinib in patients is 115 mL/min. A study of healthy volunteers using an intravenous microtracer determined the total plasma clearance to be 106 mL/min.
Protein Binding
Zongertinib is >99% bound to proteins in plasma. The specific proteins it binds to are not yet known.
Metabolism/Metabolites
Zongatinib 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 main 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 being M551(1) (monooxidation) and M656(1) (cysteine conjugate), accounting for 5.7% and 2.5% of total plasma radioactivity, respectively.
Biological Half-Life
The effective half-life of zongatinib at steady state in patients is 12 hours. A single-dose study in healthy volunteers reported a terminal half-life of 42.7 hours after intravenous injection and 45.2 hours after oral administration.

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The pharmacokinetic properties of Zongertinib are characteristic of an orally bioavailable small molecule inhibitor. Its molecular weight is 535.60. The compound is designed to have favorable drug-like properties to support oral administration and efficacy in vivo. It is soluble in DMSO at 100 mg/mL.

The Beamion LUNG-1 (NCT04886804) was an open-label, multicenter, multicohort trial evaluating the efficacy of zongertinib in patients with unresectable or metastatic HER2 (ERBB2) TKD-mutant non-squamous non-small cell lung cancer (NSCLC) who had previously received systemic therapy. The primary efficacy endpoints were objective response rate (ORR) and duration of response (DOR), assessed independently by a center-blinded method and determined according to RECIST v1.1 criteria. In 71 patients who had previously received platinum-based chemotherapy but had not received HER2-targeted tyrosine kinase inhibitors or antibody-drug conjugates (ADCs), the ORR was 75% (95% CI: 63, 83), with 58% of patients having a DOR ≥ 6 months. In 34 patients who had previously received platinum-based chemotherapy and HER2-targeting antibody-drug conjugates (ADCs), the objective response rate (ORR) was 44% (95% CI: 29, 61), with 27% of patients having a duration of response (DOR) ≥ 6 months. Prescribing information includes warnings and precautions regarding hepatotoxicity, left ventricular dysfunction, interstitial lung disease/pneumonia, and embryo-fetal toxicity. The recommended dose of zogatinib is based on body weight. For patients weighing <90 kg, the dose is 120 mg orally daily. For patients weighing ≥90 kg, the dose is 180 mg orally daily. Zogatinib can be taken with or without food and should continue until disease progression or intolerable toxicity. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-zongertinib-non-squamous-nsclc-her2-tkd-activating-mutations

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The toxicity profile of Zongertinib is expected to be favorable due to its selectivity for HER2 over EGFR, which may result in fewer off-target toxicities compared to pan-HER/EGFR inhibitors. Common adverse effects associated with HER2-targeted therapies may include diarrhea and fatigue. Preclinical studies support its safety profile.

[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.

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 insertion mutations), inhibiting downstream signaling pathways without affecting wild-type epidermal growth factor receptor (EGFR), thereby reducing related toxicities. On August 8, 2025, the US FDA granted accelerated approval to Zongertinib for the treatment of advanced non-small cell lung cancer (NSCLC) harboring HER2 tyrosine kinase domain activating mutations. Zongertinib is a kinase inhibitor. Its mechanism of action is as a HER2/Neu/cerbB2 antagonist and an inhibitor of breast cancer resistance proteins. Zongertinib is an orally bioavailable receptor tyrosine kinase inhibitor that inhibits human epidermal growth factor receptor 2 (HER2; ErbB2; HER-2) and has potential antitumor activity. After oral administration, Zongertinib covalently binds to and inhibits the activity of wild-type and mutant HER2 (including HER2 mutants with exon 20 insertion mutations). This can block HER2-mediated signaling and may lead to the death of HER2-expressing tumor cells. HER2 is a receptor tyrosine kinase that is overexpressed in a variety of tumor cell types and plays an important role in tumor cell proliferation and tumor angiogenesis. Zongertinib is a small molecule drug currently in Phase III clinical trials and has one 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 previously received systemic therapy.

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Zongertinib is a novel, selective HER2 inhibitor that is being developed for the treatment of HER2-driven cancers, including non-small cell lung cancer and breast cancer. Its covalent binding mechanism and selectivity for HER2 over EGFR are key features. It has shown promising results in preclinical studies and early-phase clinical trials.

C29H29N9O2

535.599664449692

535.244

C, 65.03; H, 5.46; N, 23.54; O, 5.97

2728667-27-2

160283094

Light yellow to green yellow solid powder

4.1

2

9

7

40

870

0

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

YSGNGFPNTLERCR-UHFFFAOYSA-N

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)

N-[1-[4-[3-methyl-4-(1-methylbenzimidazol-5-yl)oxyanilino]pyrimido[5,4-d]pyrimidin-6-yl]piperidin-4-yl]prop-2-enamide

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;

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

DMSO: 31.25 mg/mL (58.35 mM)

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.

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 (Please use freshly prepared in vivo formulations for optimal results.)