EGFR (WT); EGFR exon 20 insertion; HER2

Mobocertinib (TAK-788) is a novel irreversible EGFR TKI that has been carefully engineered to selectively and potently inhibit oncogenic variants with activating EGFRex20ins mutations while leaving wild-type EGFR alone. More potently than approved EGFR TKIs, mobocertinib inhibits the viability of different EGFRex20ins-driven cell lines over time.[1]

Mobocertinib inhibits EGFR to stop the growth of EGFRex20ins mutant tumors. The head and neck squamous cell carcinoma model (CTG-2130) with EGFRex20ins D770_N771insGL responds better to combination treatment with mobocertinib and cetuximab.

The cells are seeded into 96-well plates, treated with a series of compounds diluted three times, and allowed to incubate for seven days. For measuring viability, the CellTiter-Glo assay is utilized. IC50 values are determined by creating dose-response curves.

Female Athymic Nude-Foxn1nu mice (human NSCLC H1975 LT tumor model)
3, 10, 30 mg/kg
Oral; once daily for 20 days.

Absorption, Distribution and Excretion
The mean absolute bioavailability of mobotinib is 37%, with a median time to peak concentration (Tmax) of approximately 4 hours. Following a single oral dose of 160 mg mobotinib in fasting patients, the mean Cmax and AUC0-inf were 45.8 ng/mL and 862 ng•h/mL, respectively. Approximately 76% of the administered dose is excreted in feces (6% as unchanged drug) and only 4% in urine (1% as unchanged drug). Metabolite AP32960 accounts for 12% and 1% of the recovered dose in feces and urine, respectively, while metabolite AP32914 is below the limit of detection in both. The mean apparent volume of distribution of mobotinib at steady state is approximately 3,509 L. At steady state, the mean apparent oral clearances of mobocertinib and its two active metabolites, AP32960 and AP32914, were 138 L/hr, 149 L/hr, and 159 L/hr, respectively.
Metabolisms/Metabolites
Mobocertinib is primarily metabolized by the CYP3A enzyme to two active metabolites, AP32960 and AP32914, which are comparable in potency to mobocertinib, representing 36% and 4% of its molar AUC, respectively.
Biological Half-Life
At steady state, the mean elimination half-lives of mobocertinib and its two active metabolites, AP32960 and AP32914, were 18 hours, 24 hours, and 18 hours, respectively.

Hepatotoxicity
In premarketing clinical trials of mobocertinib in patients with non-small cell lung cancer harboring exon 20 insertion mutations in the EGRF gene, 22% of patients experienced elevated ALT levels, but these were generally self-limiting and mild. ALT elevations exceeding five times the upper limit of normal were uncommon, occurring in only 2% to 3% of treated patients. In the open-label trials supporting mobocertinib approval, no clinically significant liver injury, liver failure, or death due to liver injury was reported. Since accelerated approval of mobocertinib in 2021, there have been no published reports of clinically significant liver injury with jaundice. Probability score: E (Unproven but suspected rare cause of clinically significant liver injury). Protein Binding Mobocertinib and its metabolites bind extensively to a variety of proteins in plasma, but the specific proteins they bind to are not yet fully understood. After oral administration, the protein binding rate of mobocertinib was 99.3%, AP32960 was 99.5%, and AP32914 was 98.6%.

[1]. Cancer Discov . 2021 Jul;11(7):1672-1687.

[2]. WO 2019/222093 A1.

Mobotinib is a kinase inhibitor targeting the human epidermal growth factor receptor (EGFR). It is specifically used to treat non-small cell lung cancer (NSCLC) caused by an insertion mutation in exon 20 of the EGFR gene. These mutations typically have a poor prognosis (compared to the "classic" EGFR mutations that cause NSCLC) and are resistant to standard EGFR-targeting inhibitors. Mobotinib appears to be an effective treatment for this type of resistant NSCLC, as it inhibits EGFR exon 20 insertion mutation variants at concentrations 1.5 to 10 times lower than those required to inhibit wild-type EGFR. Mobotinib (trade name: Exkivity, Takeda Pharmaceutical Company Limited) received accelerated approval from the U.S. Food and Drug Administration (FDA) in September 2021 for the treatment of patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) harboring an EGFR exon 20 insertion mutation who have failed prior therapy.
Mobotinib is a kinase inhibitor. Its mechanism of action is as a HER1 antagonist and cytochrome P450 3A inducer. Mobotinib is an oral tyrosine kinase receptor inhibitor that targets the epidermal growth factor receptor (EGFR). In 2021, it received accelerated approval for the treatment of refractory, advanced, or metastatic non-small cell lung cancer harboring EGFR exon 20 insertion mutations, but it was withdrawn from the market in October 2023 due to a subsequent phase 3 controlled trial finding no efficacy. Among patients treated with mobotinib, 20% experienced elevated serum transaminases, but there have been no reports of clinically significant liver damage with jaundice due to its use. Mobotinib is an oral human epidermal growth factor receptor (EGFR) exon 20 insertion mutation inhibitor with antitumor activity. After oral administration, mobotinib and its active metabolites specifically and irreversibly bind to and inhibit EGFR exon 20 insertion mutations. This blocks EGFR-mediated signaling and leads to the death of tumor cells expressing exon 20 insertion mutations. Furthermore, mobotinib may also inhibit the activity of other EGFR family members, such as human epidermal growth factor receptor 2 (HER2; ERBB2) and HER4. EGFR, HER-2, and HER-4 are receptor tyrosine kinases that are frequently mutated in various tumor cell types. They play crucial roles in tumor cell proliferation and tumor angiogenesis.
See also: mobotinib succinate (in salt form).
Indications
Mobotinib is indicated for the treatment of adult patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) who carry epidermal growth factor receptor (EGFR) exon 20 insertion mutations and whose disease has progressed during or after platinum-based chemotherapy.
Mechanism of Action
Epidermal growth factor receptor (EGFR) is a transmembrane receptor that regulates signaling pathways in the control of cell proliferation. Mutations in these proteins are associated with certain types of lung cancer, including non-small cell lung cancer (NSCLC). While most EGFR mutations associated with NSCLC involve EGFR L858R point mutations or exon 19 deletions (known as "classical" EGFR mutations), the less common EGFR exon 20 insertion mutations have a very poor prognosis and are associated with resistance to standard targeted EGFR inhibitors. Mobotinib is an EGFR inhibitor that irreversibly binds to and inhibits EGFR exon 20 insertion mutations at concentrations lower than wild-type EGFR protein, with concentrations exerting pharmacological effects on the mutant being 1.5 to 10 times lower than those on the wild-type protein.

---

Pharmacodynamics
Mobotinib is an EGFR inhibitor that preferentially targets exon 20 insertion mutants. It is an oral capsule that can be taken once daily with or without food.
Mobotinib can cause concentration-dependent QTc interval prolongation, which may lead to life-threatening complications such as torsades de pointes. Patients with baseline risk factors for QTc prolongation should consider alternative medications or be closely monitored throughout treatment. Concomitant use with other medications that can prolong the QTc interval, as well as CYP3A inhibitors, should be avoided, as these may increase the concentration of mobotinib, thereby increasing the risk of QTc prolongation.

C₃₂H₃₉N₇O₄

585.6966

585.31

C, 65.62; H, 6.71; N, 16.74; O, 10.93

1847461-43-1

Mobocertinib succinate;2389149-74-8;Mobocertinib mesylate;2389149-85-1

118607832

Off-white to light yellow solid powder

4.4

2

9

13

43

935

0

AZSRSNUQCUDCGG-UHFFFAOYSA-N

InChI=1S/C32H39N7O4/c1-9-29(40)34-24-16-25(28(42-8)17-27(24)38(6)15-14-37(4)5)35-32-33-18-22(31(41)43-20(2)3)30(36-32)23-19-39(7)26-13-11-10-12-21(23)26/h9-13,16-20H,1,14-15H2,2-8H3,(H,34,40)(H,33,35,36)

propan-2-yl 2-[4-[2-(dimethylamino)ethyl-methylamino]-2-methoxy-5-(prop-2-enoylamino)anilino]-4-(1-methylindol-3-yl)pyrimidine-5-carboxylate

TAK-788; AP-32788; TAK 788; AP32788; TAK788; AP 32788

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: ~25 mg/mL (42.7 mM）

Solubility in Formulation 1: ≥ 2.5 mg/mL (4.27 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.

---

Solubility in Formulation 2: ≥ 1.25 mg/mL (2.13 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 12.5 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

---

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