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| Targets |
Mobocertinib succinate targets the epidermal growth factor receptor (EGFR) and HER2 oncogenic mutants, including exon 20 insertion mutations. It acts as an irreversible inhibitor, forming a covalent bond with a cysteine residue in the ATP-binding pocket of the kinase domain. This covalent binding results in sustained inhibition of the kinase activity, blocking downstream signaling pathways such as the MAPK and PI3K/AKT pathways that promote cell proliferation and survival. The compound exhibits selectivity for EGFRex20ins mutants over wild-type EGFR, which is important for reducing off-target toxicity.
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| ln Vitro |
LU0387 (NPH) cells are inhibited by mobocertinib succinate (1.5 nM-10 μM; 7 days) with an IC50 of 21 nM [1]. More powerful than WT EGFR (A431 (WT)), mobocertinib succinate (2 h) effectively suppresses EGFR with common activating mutations (HCC827 (D), HCC4011 (L)), or with the T790M mutation (H1975 (LT)) [1]. In CUTO14 (ASV) cells, mobocertinib succinate (0.1 nM-1 μM; 6 hours) suppresses pEGFR and pERK1/2 [1]. Over a 6-hour period, mobocertinib succinate (0.3 nM-1 μM) suppresses downstream signaling and EGFR [1]. H1781 (HER2 exon 20G776>VC) and Ba/F3 (HER2 exon 20YVMA) cells' HER2 signaling is inhibited by mobocertinib succinate (0.01, 0.1, and 1 μM; 6 hours) [2].
In vitro, Mobocertinib succinate potently inhibits EGFR exon 20 insertion mutants with high selectivity over wild-type EGFR. In cell-based assays, the compound demonstrates nanomolar IC50 values against cell lines harboring EGFRex20ins mutations, while showing significantly reduced activity against wild-type EGFR-expressing cells. This selectivity translates to potent antiproliferative effects in cancer cells driven by these mutations. The irreversible binding mechanism ensures prolonged target inhibition, which is a key factor in its efficacy. The compound also inhibits HER2 mutants, broadening its potential application. |
| ln Vivo |
Mobocertinib succinate (oral; 3, 10, 30 mg/kg; once daily for 20 days) greatly suppresses the growth of tumors [1].
In vivo, Mobocertinib succinate has demonstrated significant antitumor efficacy in xenograft mouse models bearing EGFRex20ins-driven tumors. Oral administration of the compound at doses of 3, 10, and 30 mg/kg once daily for 20 days resulted in dose-dependent tumor growth inhibition. The compound was well-tolerated at these doses, with no significant body weight loss observed. The in vivo efficacy is consistent with its potent in vitro activity and favorable pharmacokinetic properties. These preclinical findings supported the clinical development of Mobocertinib for the treatment of NSCLC with EGFRex20ins mutations. |
| Enzyme Assay |
In vitro enzyme/receptor binding assays for Mobocertinib succinate involve measuring its inhibition of EGFR kinase activity. The assay is typically performed using recombinant EGFR kinase domain proteins in the presence of ATP and a peptide substrate. The phosphorylation of the substrate is measured using a luminescent or fluorescent readout, and the IC50 value is calculated from dose-response curves. Selectivity is assessed by testing the compound against a panel of other kinases, including wild-type EGFR and HER2. The irreversible nature of the binding can be confirmed by washout experiments, where the compound's inhibitory activity persists after removal of the free compound.
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| Cell Assay |
Cell viability assay [1]
Cell Types: LU0387 (NPH) Cell Tested Concentrations: 1.5 nM-10 μM Incubation Duration: 7 days Experimental Results: Good inhibitory activity against LU0387 (NPH) cells with an IC50 of 21 nM. Cell viability assay[1] Cell Types: A431 (WT), HCC827 (D), HCC4011 (L), H1975 (LT) Cell Tested Concentrations: Incubation Duration: 2 hrs (hours) Experimental Results: Inhibition of EGFR with common activation of HCC827 (D) mutations, the T790M mutation in HCC4011 (L) cells and H1975 (LT) cells had IC50s of 4, 1.3, and 9.8 nM, respectively, which was more potent than WT EGFR (A431 (WT); IC50 of 35 nM). Western Blot Analysis[1] Cell Types: CUTO14 (ASV) Cell Tested Concentrations: 0.1 nM-1 μM Incubation Duration: 6 hrs (hours) Experimental Results: Strong inhibition of EGFR signaling, reaching 80% inhibition of phosphorylated EGFR (pEGFR) at a concentration of 100 and 100% are nM and 1 μM respectively. Western Blot Analysis[1] Cell Types: HCC827 (D), HCC4011 (L), H1975 (LT) Cell Tested Concentrations: 0.3 nM-1 μM Incubation Duration: 6 hrs (hours) Experimental Results: Potently inhibited EGFR and downstream signaling in HCC827 (D), HCC4011 (L) and H1975 (LT) cells. Western Blot Analysis[2] Cell Types: H1781 (HER2 Exon 20G776>VC), Ba/F3 (HER2 exon 20YVMA) cells Tested Concentrations: 0.01, 0.1 and 1 μM Incubation Duration: 6 h Experimental Results: Inhibited HER2 signaling in H1781 and Ba/F3-HER2 exon 20YVMA mutant cells at 0.1 μM with Dramatically diminished phosphorylations of HER2, AKT, and ERK1/2 in a dose-dependent manner. In vitro cellular experiments for Mobocertinib succinate are performed using cancer cell lines harboring EGFRex20ins mutations. Cells are treated with varying concentrations of the compound for 72-96 hours, and cell viability is measured using an MTT or CellTiter-Glo assay. The IC50 values are calculated to determine the potency of the compound. To confirm the mechanism of action, the phosphorylation of EGFR and downstream signaling proteins such as AKT and ERK is assessed by Western blot. The selectivity of the compound is confirmed by testing it against wild-type EGFR-expressing cells. |
| Animal Protocol |
Animal/Disease Models: Female athymic Nude-Foxn1nu (nude) mice (human NSCLC H1975 LT tumor model) [1].
Doses: 3, 10, 30 mg/kg Route of Administration: Oral; one time/day for 20 days. Experimental Results: Relative to tumor size in the vehicle group, mean tumor volume was diminished by 44% and 92% at 3 mg/kg and 10 mg/kg, respectively. 30 mg/kg induced 76% tumor regression relative to pre-treatment tumor size. In vivo animal studies for Mobocertinib succinate are conducted using immunocompromised mice bearing subcutaneous human tumor xenografts with EGFRex20ins mutations. Tumor-bearing mice are randomized into treatment and control groups and administered the compound orally once daily at various doses. Tumor volumes and body weights are measured twice weekly to monitor antitumor efficacy and toxicity. At the end of the study, tumors are collected for histopathological analysis and to measure biomarkers of target engagement. Pharmacokinetic parameters are also evaluated from plasma samples collected at multiple time points post-administration. |
| ADME/Pharmacokinetics |
Mobocertinib succinate exhibits favorable pharmacokinetic properties following oral administration. The compound is rapidly absorbed, with peak plasma concentrations (Cmax) achieved within 2-4 hours. It has a moderate half-life, allowing for once-daily dosing. The compound is extensively metabolized in the liver, primarily by cytochrome P450 enzymes, and its metabolites are excreted via the biliary and renal routes. The succinate salt form improves the compound's solubility and bioavailability compared to the free base. The pharmacokinetic profile of Mobocertinib supports its clinical use in NSCLC patients.
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| Toxicity/Toxicokinetics |
The toxicity profile of Mobocertinib succinate has been characterized in preclinical and clinical studies. Common adverse effects include diarrhea, rash, nausea, and stomatitis, which are consistent with EGFR inhibition. More serious toxicities, such as interstitial lung disease (ILD), have also been reported. The compound's selectivity for EGFRex20ins mutants over wild-type EGFR is designed to reduce the severity of these toxicities. In preclinical toxicology studies, the compound was well-tolerated at therapeutic doses, with no significant adverse effects observed. Ongoing monitoring of patients is essential to manage these adverse effects.
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| References |
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| Additional Infomation |
Mobocertinib succinate is the succinate form of Mobocertinib, an orally administered and potent antitumor drug that inhibits human epidermal growth factor receptor (EGFR) exon 20 insertion mutations. After oral administration, Mobocertinib 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, Mobocertinib 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: Mobocertinib (containing the active moiety). Mobocertinib succinate is a first-in-class, orally active, irreversible inhibitor of EGFR and HER2 exon 20 insertion mutants. It received FDA approval for the treatment of adult patients with locally advanced or metastatic NSCLC with EGFRex20ins mutations whose disease has progressed on or after platinum-based chemotherapy. This approval was based on results from a Phase 1/2 clinical trial demonstrating a meaningful objective response rate and durable responses. Mobocertinib represents a significant advancement in the treatment of NSCLC and highlights the potential of targeted therapy for genomically defined patient populations. |
| Molecular Formula |
C36H45N7O8
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|---|---|
| Molecular Weight |
703.7846
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| Exact Mass |
703.332
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| CAS # |
2389149-74-8
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| Related CAS # |
Mobocertinib;1847461-43-1;Mobocertinib mesylate;2389149-85-1
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| PubChem CID |
146026179
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| Appearance |
White to yellow solid powder
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| Hydrogen Bond Donor Count |
4
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| Hydrogen Bond Acceptor Count |
13
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| Rotatable Bond Count |
16
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| Heavy Atom Count |
51
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| Complexity |
1030
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| Defined Atom Stereocenter Count |
0
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| SMILES |
O(C([H])([H])[H])C1C([H])=C(C(=C([H])C=1N([H])C1=NC([H])=C(C(=O)OC([H])(C([H])([H])[H])C([H])([H])[H])C(C2=C([H])N(C([H])([H])[H])C3=C([H])C([H])=C([H])C([H])=C23)=N1)N([H])C(C([H])=C([H])[H])=O)N(C([H])([H])[H])C([H])([H])C([H])([H])N(C([H])([H])[H])C([H])([H])[H].O([H])C(C([H])([H])C([H])([H])C(=O)O[H])=O
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| InChi Key |
YXYAEUMTJQGKHS-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C32H39N7O4.C4H6O4/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;5-3(6)1-2-4(7)8/h9-13,16-20H,1,14-15H2,2-8H3,(H,34,40)(H,33,35,36);1-2H2,(H,5,6)(H,7,8)
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| Chemical Name |
butanedioic acid;propan-2-yl 2-[4-[2-(dimethylamino)ethyl-methylamino]-2-methoxy-5-(prop-2-enoylamino)anilino]-4-(1-methylindol-3-yl)pyrimidine-5-carboxylate
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| HS Tariff Code |
2934.99.9001
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| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month Note: Please store this product in a sealed and protected environment, avoid exposure to moisture. |
| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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| Solubility (In Vitro) |
DMSO : ~125 mg/mL (~177.61 mM)
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.08 mg/mL (2.96 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 20.8 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. Solubility in Formulation 2: ≥ 2.08 mg/mL (2.96 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 20.8 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.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 1.4209 mL | 7.1045 mL | 14.2090 mL | |
| 5 mM | 0.2842 mL | 1.4209 mL | 2.8418 mL | |
| 10 mM | 0.1421 mL | 0.7104 mL | 1.4209 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.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
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