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 mobocertinib is 37% and the median Tmax is approximately 4 hours. Following a single oral dose of 160mg of mobocertinib to fasted patients, the mean Cmax and AUC0-inf were 45.8 ng/mL and 862 ng•h/mL, respectively.
Following oral administration of mobocertinib, approximately 76% of the administered dose was recovered in the feces (6% as unchanged parent drug) with only 4% recovered in the urine (1% as unchanged parent drug). The metabolite AP32960 comprised 12% and 1% of the recovered dose found in the feces and urine, respectively, while the metabolite AP32914 was below the detection limit in both.
The mean apparent volume of distribution of mobocertinib was approximately 3,509 L at steady-state.
At steady-state, the mean apparent oral clearance of mobocertinib and its two active metabolites, AP32960 and AP32914, was 138 L/hr, 149 L/hr, and 159 L/hr, respectively.

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Metabolism / Metabolites
Mobocertinib is metabolized primarily by CYP3A enzymes to two active metabolites, AP32960 and AP32914, which are equipotent to mobocertinib and account for 36% and 4% of its combined molar AUC, respectively.

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Biological Half-Life
At steady-state, the mean elimination half-life of mobocertinib and its two active metabolites, AP32960 and AP32914, was 18 hours, 24 hours, and 18 hours, respectively.

Hepatotoxicity
In the prelicensure clinical trials of mobocertinib in patients with NSCLC harboring the exon 20 insertion mutation in EGRF, ALT elevations arose in 22% of patients but were usually self-limited and mild. ALT elevations above 5 times the upper limit of normal (ULN) were uncommon, being found in 2% to 3% of treated patients. In the open label trials supporting the approval of mobocertinib, there were no instances of clinically apparent liver injury, hepatic failure, or deaths from liver injury. Since the accelerated approval of mobocertinib in 2021 there were no published case reports of clinically apparent liver injury with jaundice.
Likelihood score: E* (unproven but suspected rare cause of clinically apparent liver injury).

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Protein Binding
Mobocertinib and its metabolites are extensively protein-bound in plasma, although the specific proteins to which they bind have not been elucidated. Following oral administration, mobocertinib is 99.3% protein-bound, AP32960 is 99.5% protein-bound, and AP32914 is 98.6% protein-bound.

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

[2]. WO 2019/222093 A1.

Mobocertinib is a kinase inhibitor targeted against human epidermal growth factor receptor (EGFR). It is used specifically in the treatment of non-small cell lung cancer (NSCLC) caused by exon 20 insertion mutations in the EGFR gene, which are typically associated with a poorer prognosis (as compared to "classical" EGFR mutants causing NSCLC) and are associated with resistance to standard targeted EGFR inhibitors. Mobocertinib appears to be an effective means of treating this otherwise treatment-resistant NSCLC, exerting an inhibitory effect on EGFR exon 20 insertion mutant variants at concentrations 1.5- to 10-fold lower than those required to inhibit wild-type EGFR. Mobocertinib, under the brand name Exkivity (Takeda Pharmaceuticals Inc.), was granted accelerated approval by the FDA in September 2021 for the treatment of locally advanced or metastatic NSCLC in patients with EGFR exon 20 insertion mutations who have failed previous therapies.
Mobocertinib is a Kinase Inhibitor. The mechanism of action of mobocertinib is as a HER1 Antagonist, and Cytochrome P450 3A Inducer.
Mobocertinib is an oral tyrosine kinase receptor inhibitor that targets the epidermal growth factor receptor (EGFR) and was given accelerated approved for use in refractory, advanced or metastatic non-small cell lung cancer with EGFR exon 20 insertion mutations in 2021, but was subsequently withdrawn from use in October 2023 because of lack of efficacy found in a subsequent phase 3 controlled trial. Serum aminotransferase elevations occurred in 20% of patients treated with mobocertinib, but no episodes of clinically apparent liver injury with jaundice have been reported with its use.
Mobocertinib is an orally available inhibitor of human epidermal growth factor receptor (EGFR) exon 20 insertion mutations, with antineoplastic activity. Upon oral administration, mobocertinib, and its active metabolites, specifically and irreversibly binds to and inhibits exon 20 insertion mutations of EGFR. This prevents EGFR-mediated signaling and leads to cell death in tumor cells expressing exon 20 insertion mutations. In addition, mobocertinib may inhibit the activity of other EGFR family members, such as human epidermal growth factor receptor 2 (HER2; ERBB2) and HER4. EGFR, HER-2 and -4 are receptor tyrosine kinases often mutated in numerous tumor cell types. They play key roles in tumor cell proliferation and tumor vascularization.
See also: Mobocertinib Succinate (has salt form).

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Drug Indication
Mobocertinib is indicated for the treatment of adult patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) exon 20 insertion mutations whose disease has progressed on or after platinum-based chemotherapy.

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Mechanism of Action
The epidermal growth factor receptor (EGFR) is a transmembrane receptor that regulates signaling pathways in the control of cellular proliferation. Mutations in these proteins have been associated with certain types of lung cancer, including non-small cell lung cancer (NSCLC). While the majority of _EGFR_ mutations associated with NSCLC involve the _EGFR_ L858R point mutation or exon 19 deletions (referred to as "classical" _EGFR_ mutations), less common _EGFR_ exon 20 insertion mutations carry a particularly poor prognosis and are associated with resistance to standard targeted EGFR inhibitors. Mobocertinib is an inhibitor of EGFR that irreversibly binds to and inhibits EGFR exon 20 insertion mutations at lower concentrations than wild-type EGFR proteins, exerting a pharmacologic effect on mutant variants at concentrations 1.5- to 10-fold lower than on wild-type proteins.

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Pharmacodynamics
Mobocertinib is an inhibitor of EGFR that preferentially targets exon 20 insertion mutant variants. It is available as an oral capsule taken with or without food once daily. Mobocertinib can cause a concentration-dependent increase in QTc interval 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 monitored carefully throughout therapy. The use of concomitant QTc-prolonging medications should be avoided, as should concomitant inhibitors of CYP3A, as these may increase the concentration of mobocertinib and thus 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.

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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.

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