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Mobocertinib succinate, the succinate salt of Mobocertinib (TAK788; AP32788;
Exkivity), is an approved medication for the treatment of non-small cell lung cancer
(NSCLC). It acts as an irreversible inhibitor of EGFR and HER2 oncogenic mutants (e.g. exon 20 insertions),
and shows high selectivity over WT EGFR. As of 9/15/2021, mobocertinib has been approved by FDA via the acceleration channel for treating metastatic NSCLC with EGFR exon 20 insertion mutations.
| 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].
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|---|---|
| ln Vivo |
Mobocertinib succinate (oral; 3, 10, 30 mg/kg; once daily for 20 days) greatly suppresses the growth of tumors [1].
|
| 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. |
| 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. |
| References |
|
| Additional Infomation |
Mobocertinib Succinate is the succinate salt form of mobocertinib, 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 (has active moiety). |
| Molecular Formula |
C36H45N7O8
|
|---|---|
| Molecular Weight |
703.7846
|
| Exact Mass |
703.332
|
| CAS # |
2389149-74-8
|
| Related CAS # |
Mobocertinib;1847461-43-1;Mobocertinib mesylate;2389149-85-1
|
| PubChem CID |
146026179
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| Appearance |
White to yellow solid powder
|
| Hydrogen Bond Donor Count |
4
|
| Hydrogen Bond Acceptor Count |
13
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| Rotatable Bond Count |
16
|
| Heavy Atom Count |
51
|
| Complexity |
1030
|
| Defined Atom Stereocenter Count |
0
|
| 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
|
| InChi Key |
YXYAEUMTJQGKHS-UHFFFAOYSA-N
|
| 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)
|
| 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
|
| 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)
|
| 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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