ErbBs/epidermal growth factor receptor (EGFR) exon 20 insertion mutations; BTK
Sunvozertinib targets the epidermal growth factor receptor (EGFR) and HER2, with particular potency against mutant forms including EGFR exon 20 NPH insertion (IC50 = 20.4 nM), EGFR exon 20 ASV insertion (IC50 = 20.4 nM), EGFR L858R/T790M (IC50 = 1.1 nM), and HER2 exon 20 YVMA (IC50 = 7.5 nM). It also inhibits BTK. As an irreversible inhibitor, it forms a covalent bond with the kinase domain. It exhibits reduced activity against wild-type EGFR (IC50 = 80.4 nM in A431 cells).

Sunvozertinib's GI50 values were 60.4, 83.2, 3.3, 101.3, and 47.1 nM A431, respectively, against the EGFR exon NPH insertion, EGFR exon 20 ASV insertion, EGFR L858R and T790M mutations, Her2 Exon20 YVMA, and EGFR WT. For BTK WT OCI -LY-10, BTK WT TMD-8, BTK WT Ri-1, and non-BCR activated DB, the GI50 of sunvozertinib was 3.2, 5.8, 51.3, and 1983.5 nM, respectively [1]. p-BTK is inhibited by sunvozertinib at an IC50 of 1.6 nM[1].
In vitro, Sunvozertinib demonstrates strong inhibitory activity against a range of clinically relevant EGFR mutations. It shows IC50 values of 20.4 nM for EGFR exon 20 NPH insertion, 20.4 nM for EGFR exon 20 ASV insertion, 1.1 nM for EGFR L858R/T790M, and 7.5 nM for HER2 exon 20 YVMA mutation. It exhibits reduced activity against wild-type EGFR (IC50 = 80.4 nM in A431 cells), supporting its selectivity for mutant forms. The compound's potent anti-proliferative activity is selective for mutant EGFR-driven cells.

In vivo, Sunvozertinib is orally bioavailable and has demonstrated antitumor activity in preclinical models of NSCLC with EGFR or HER2 exon 20 alterations. It shows strong inhibition of EGFR phosphorylation and significant anti-tumor effects in xenograft models. The compound has been investigated in clinical trials and received accelerated FDA approval for adult patients with locally advanced or metastatic NSCLC with EGFR exon 20 insertion mutations who have progressed on or after platinum-based chemotherapy.

For receptor binding studies, EGFR kinase assays are performed using recombinant EGFR protein (wild-type or mutant variants) incubated with a peptide substrate and ATP. The test compound is added at various concentrations (0.1-1000 nM). Kinase activity is measured using radioactive ATP incorporation or luminescent ADP detection assays. IC50 values are calculated by fitting dose-response curves. HER2 and BTK inhibition are assessed using similar biochemical assays with recombinant proteins.

For cell proliferation assays, cancer cell lines expressing EGFR mutations (such as Ba/F3 cells engineered to express EGFR exon 20 insertions, NCI-H1975 for EGFR L858R/T790M, or A431 for wild-type EGFR) are seeded in 96-well plates and treated with Sunvozertinib at concentrations ranging from 0.01-10 µM for 72 hours. Cell viability is assessed using CellTiter-Glo or MTT assays. IC50 values are calculated from dose-response curves.

For in vivo efficacy studies, immunodeficient mice are implanted with Ba/F3 cells expressing EGFR mutations (CDX) or patient-derived NSCLC xenografts (PDX) harboring EGFR exon 20 insertions or other mutations. When tumors reach approximately 100-200 mm³, mice are randomized and treated with Sunvozertinib via oral gavage at doses determined from pharmacokinetic studies. Tumor volumes are measured twice weekly. At study endpoint, tumors are collected for Western blot analysis of EGFR phosphorylation.

Sunvozertinib is orally bioavailable with favorable pharmacokinetic properties suitable for once-daily oral dosing. The compound is soluble in DMSO. Storage is recommended at -20°C for 3 years (powder) or -20°C for 6 months (solution). After oral administration, it shows good absorption and tissue distribution. Detailed PK parameters including half-life, Cmax, AUC, and protein binding would be available from clinical data and primary literature.

Prescribing information for taliprettinib includes warnings and precautions regarding hepatotoxicity, interstitial lung disease/pneumonia, QTc interval prolongation, hyperuricemia, myalgia due to elevated creatine phosphokinase, fractures, and embryo-fetal toxicity. The recommended dose of taliprettinib is 600 mg orally once daily on an empty stomach (without food for at least 2 hours before or after administration) until disease progression or unacceptable toxicity occurs.
Sunvozertinib is generally well-tolerated in clinical studies. The compound's selectivity for mutant EGFR over wild-type EGFR (IC50 = 80.4 nM in A431 cells) may reduce on-target toxicities associated with wild-type EGFR inhibition. In preclinical toxicology studies, it has shown an acceptable safety profile. As an FDA-approved drug, comprehensive toxicology data are available from regulatory submissions. Standard safety precautions should be followed when handling the research-grade compound.

[1]. Erbb/btk inhibitors. WO2019149164A1.

Sunvozertinib is an oral, irreversible dual kinase inhibitor of epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor 2 (HER2), exhibiting similar activity against certain activating mutations, including exon 20 insertion mutations (exon20ins), and possessing potential antitumor activity. After oral administration, Sunvozertinib binds to and inhibits the activity of both EGFR and HER2, thereby suppressing tumor growth and angiogenesis, and causing regression in tumors expressing EGFR/HER2. EGFR and HER2 are receptor tyrosine kinases that play important roles in tumor cell proliferation and tumor angiogenesis. Compared to other drugs targeting exon20ins mutations, Sunvozertinib appears to have higher selectivity for mutant EGFR than for wild-type (wt) EGFR. This may mitigate dose-limiting toxicities associated with wtEGFR and may allow for the administration of the required dose of sunvozertinib.

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Drug Indication
Treatment of Non-Small Cell Lung Cancer
The efficacy of this drug was evaluated in patients with locally advanced or metastatic, ROS1-positive NSCLC in two multicenter, single-arm, open-label clinical trials, TRUST-I (NCT04395677) and TRUST-II (NCT04919811). The evaluable population included 157 patients who had not previously received a ROS1 tyrosine kinase inhibitor (TKI) (103 in TRUST-I; 54 in TRUST-II) and 113 patients who had previously received one ROS1 TKI (66 in TRUST-I; 47 in TRUST-II). Patients may have previously received chemotherapy for advanced disease. The primary efficacy endpoints were confirmed overall response rate (ORR) and duration of response (DOR), as determined by blinded, independent central review according to RECIST v1.1 criteria. For treatment-naïve patients, the ORR in the TRUST-I study was 90% (95% CI: 83, 95), and the ORR in the TRUST-II study was 85% (95% CI: 73, 93), with 72% and 63% of responders having a DOR ≥ 12 months, respectively. For patients who had previously received TKI therapy, the ORR in the TRUST-I study was 52% (95% CI: 39, 64), and the ORR in the TRUST-II study was 62% (95% CI: 46, 75), with 74% and 83% of responders having a DOR ≥ 6 months, respectively.
Sunvozertinib (DZD-9008) is an oral, potent, irreversible EGFR/HER2 inhibitor targeting EGFR exon 20 insertions and other clinically relevant mutations. It received FDA accelerated approval on July 2, 2025 for adult patients with NSCLC with EGFR exon 20 insertion mutations who have progressed on or after platinum-based chemotherapy. The compound shows IC50 values of 20.4 nM (EGFR exon 20 NPH), 20.4 nM (EGFR exon 20 ASV), 1.1 nM (EGFR L858R/T790M), and 7.5 nM (HER2 exon 20 YVMA). It is an approved therapeutic for NSCLC.

C29H35CLFN7O3

584.084708452225

583.247

C, 59.63; H, 6.04; Cl, 6.07; F, 3.25; N, 16.79; O, 8.22

2370013-12-8

(S)-Sunvozertinib;2370013-49-1

139377809

Off-white to light brown solid powder

5

4

10

10

41

885

1

CC(C)(C1=CC(=C(C=C1NC2=NC(=NC=C2)NC3=C(C=C(C(=C3)NC(=O)C=C)N4CC[C@H](C4)N(C)C)OC)Cl)F)O

BTMKEDDEMKKSEF-QGZVFWFLSA-N

InChI=1S/C29H35ClFN7O3/c1-7-27(39)34-22-14-23(25(41-6)15-24(22)38-11-9-17(16-38)37(4)5)35-28-32-10-8-26(36-28)33-21-13-19(30)20(31)12-18(21)29(2,3)40/h7-8,10,12-15,17,40H,1,9,11,16H2,2-6H3,(H,34,39)(H2,32,33,35,36)/t17-/m1/s1

N-{5-({4-[5-chloro-4-fluoro-2-(2-hydroxypropan-2-yl)anilino]pyrimidin-2-yl}amino)-2-[(3R)-3-(dimethylamino)pyrrolidin-1-yl]-4-methoxyphenyl}prop-2-enamide

DZD-9008; Sunvozertinib; DZD 9008; sunvozertinib; 2370013-12-8; Sunvozertinib [INN]; L1Q2K5JYO8; DZD9008

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 : ~50 mg/mL (~85.60 mM)

Solubility in Formulation 1: ≥ 2.5 mg/mL (4.28 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% 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 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 2: 2.5 mg/mL (4.28 mM) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), suspension solution; with ultrasonication.
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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Solubility in Formulation 3: ≥ 2.5 mg/mL (4.28 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (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 corn oil and mix evenly.

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