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BLU-945 (BLU945) is afourth-generationEGFR tyrosine kinase inhibitor with intracranial and anticancer activity.It effectively inhibitsEGFR+/T790M and EGFR+/T790M/C797S resistance mutants that maintains activity against the sensitizing mutations, especially L858R. Pre-clinical efficacy and safety studies supported progression of BLU-945 into clinical studies, and it is currently in phase 1/2 clinical trials for treatment-resistant EGFR-driven NSCLC.
| ln Vitro |
BLU-945 has inhibitory effect with IC50 values ranging from 1.2-4.4 nM against EGFRm/T790M double mutant and EGFRm/T790M/C797Striple mutant[2]. In EGFR L858R/T790M/C797S and EGFR ex19del/T790M/C797S mutant cell lines, BLU-945 (0-10 mM, 4 hours) suppresses EGFR phosphorylation [2].
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| ln Vivo |
BLU-945 (interface, 0-100 mg/kg; bid) demonstrates strong, increased suppression of EGFR staining and anti-tumor action in Osimertinib-primed triple mutant Ba/F3 CDX and PDCX mice [2].
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| Animal Protocol |
Animal/Disease Models: Triple mutation osimertinib-resistant Ba/F3 CDX and PDCX model [2]
Doses: 0-100 mg/kg Route of Administration: po (po (oral gavage)) twice (two times) daily Experimental Results: Osimertinib-resistant EGFR ex19del/T790M/C797S Significant tumor regression was demonstrated in PDCX. |
| References | |
| Additional Infomation |
Tigozertinib is a fourth-generation, orally bioavailable, mutant-selective, epidermal growth factor receptor (EGFR) inhibitor, with potential antineoplastic activity. Upon oral administration, tigozertinib targets, binds to and inhibits the activity of EGFR with C797S triple mutations including ex19del/T790M/C797S and L858R/T790M/C797S, thereby preventing EGFR-mediated signaling. This may both induce cell death and inhibit tumor growth in EGFR-overexpressing tumor cells. EGFR, a receptor tyrosine kinase mutated in many tumor cell types, plays a key role in tumor cell proliferation and tumor vascularization. BLU-945 inhibits mutated forms of EGFR with C797S mutation, which prevents covalent bond formation with third-generation EGFR inhibitors leading to drug resistance. BLU-945 may have enhanced anti-tumor effects in tumors with C797S-mediated resistance when compared to other EGFR tyrosine kinase inhibitors.
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| Molecular Formula |
C28H37FN6O3S
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|---|---|
| Molecular Weight |
556.70
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| Exact Mass |
556.26
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| Elemental Analysis |
C, 60.41; H, 6.70; F, 3.41; N, 15.10; O, 8.62; S, 5.76
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| CAS # |
2660250-10-0
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| PubChem CID |
156538665
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| Appearance |
Light yellow to yellow solid powder
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| LogP |
4.6
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| Hydrogen Bond Donor Count |
1
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| Hydrogen Bond Acceptor Count |
10
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| Rotatable Bond Count |
8
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| Heavy Atom Count |
39
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| Complexity |
922
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| Defined Atom Stereocenter Count |
4
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| SMILES |
C[C@@H]1[C@H](CN1C2=C3C=NC(=CC3=C(C=C2)C(C)C)NC4=NC(=NC=C4)N5CC[C@H]([C@H](C5)F)OC)CS(=O)(=O)C
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| InChi Key |
LIMFPAAAIVQRRD-BCGVJQADSA-N
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| InChi Code |
InChI=1S/C28H37FN6O3S/c1-17(2)20-6-7-24(35-14-19(18(35)3)16-39(5,36)37)22-13-31-27(12-21(20)22)32-26-8-10-30-28(33-26)34-11-9-25(38-4)23(29)15-34/h6-8,10,12-13,17-19,23,25H,9,11,14-16H2,1-5H3,(H,30,31,32,33)/t18-,19-,23+,25-/m1/s1
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| Chemical Name |
N-[2-[(3S,4R)-3-fluoro-4-methoxypiperidin-1-yl]pyrimidin-4-yl]-8-[(2R,3S)-2-methyl-3-(methylsulfonylmethyl)azetidin-1-yl]-5-propan-2-ylisoquinolin-3-amine
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| Synonyms |
BLU-945; BLU 945; BLU945; tigozertinib
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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: This product requires protection from light (avoid light exposure) during transportation and storage. |
| 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 : ~100 mg/mL (~179.63 mM)
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|---|---|
| Solubility (In Vivo) |
Solubility in Formulation 1: 2.5 mg/mL (4.49 mM) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), suspension solution; with sonication.
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: 2.08 mg/mL (3.74 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 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. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 1.7963 mL | 8.9815 mL | 17.9630 mL | |
| 5 mM | 0.3593 mL | 1.7963 mL | 3.5926 mL | |
| 10 mM | 0.1796 mL | 0.8981 mL | 1.7963 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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