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| 1mg |
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| 5mg |
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| 10mg |
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| Targets |
BLU-945 targets EGFR mutants including the triple-mutant EGFR (activating mutation + T790M + C797S) and EGFR+/T790M mutations, with IC50 <1 nM. It specifically inhibits EGFR variants harboring activating mutations such as L858R or exon 19 deletions, as well as resistance-associated mutations including T790M and C797S. BLU-945 spares wild-type EGFR, reducing EGFR-mediated on-target toxicities. As a reversible inhibitor, it does not rely on covalent binding for activity.
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| 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].
In vitro, BLU-945 has inhibitory effects with IC50 values ranging from 1.2-4.4 nM against EGFRm/T790M double mutant and EGFRm/T790M/C797S triple mutant. In EGFR L858R/T790M/C797S and EGFR ex19del/T790M/C797S mutant cell lines, BLU-945 (0-10 mM, 4 hours) suppresses EGFR phosphorylation. It effectively inhibits EGFR with L858R and/or exon 19 deletion mutation, T790M mutation, and C797S mutation. The compound's mutant selectivity and potency make it valuable for overcoming resistance. |
| 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].
In vivo, BLU-945 demonstrates strong, increased suppression of EGFR staining and anti-tumor action in osimertinib-primed triple mutant Ba/F3 CDX and patient-derived xenograft (PDX) models in mice at doses of 0-100 mg/kg, administered orally twice daily. Osimertinib-resistant EGFR ex19del/T790M/C797S showed significant tumor regression in PDX models. BLU-945 has progressed into phase 1/2 clinical trials for treatment-resistant EGFR-driven NSCLC. |
| Enzyme Assay |
For in vitro kinase assays, recombinant EGFR proteins (wild-type and mutant variants) are incubated with a peptide substrate and ATP in kinase assay buffer. The test compound is added at various concentrations (0.001-1000 nM). Kinase activity is measured using radioactive ATP incorporation or luminescent ADP detection assays. IC50 values are calculated by fitting dose-response curves. BLU-945 shows IC50 values of 1.2-4.4 nM against EGFR mutants.
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| Cell Assay |
For cell-based assays, NSCLC cell lines expressing EGFR mutations (such as Ba/F3 cells engineered to express EGFR mutants, or H1975 cells for EGFR L858R/T790M) are treated with BLU-945 at concentrations ranging from 0.001-10 µM for 72 hours. EGFR phosphorylation is assessed by Western blotting. Cell viability is measured using CellTiter-Glo or MTT assays. IC50 values are calculated from dose-response curves. The compound's selectivity for mutant EGFR over wild-type EGFR can be confirmed in A431 cells expressing wild-type EGFR.
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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. For in vivo efficacy studies, immunodeficient mice are implanted with Ba/F3 cells expressing triple-mutant EGFR (CDX) or patient-derived NSCLC xenografts (PDX) harboring EGFR mutations. When tumors reach a predetermined size, mice are randomized and treated with BLU-945 via oral gavage at doses of 0-100 mg/kg twice daily. Tumor volumes are measured twice weekly. At study endpoint, tumors are collected for Western blot analysis of EGFR phosphorylation and histopathological examination. |
| ADME/Pharmacokinetics |
BLU-945 is orally bioavailable with favorable pharmacokinetic properties. It is a fourth-generation EGFR inhibitor with intracranial activity, suggesting good brain penetration. The compound is soluble in DMSO. Storage is recommended at -20°C for long-term stability. Further detailed PK parameters including half-life, Cmax, AUC, and protein binding would be available from the primary literature and clinical data.
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| Toxicity/Toxicokinetics |
In preclinical studies, BLU-945 is well-tolerated at efficacious doses. The compound's selectivity for mutant EGFR over wild-type EGFR reduces EGFR-mediated on-target toxicities. In clinical trials, the compound's safety profile is being evaluated. Common adverse effects associated with EGFR inhibitors include skin rash, diarrhea, and stomatitis. Comprehensive toxicology data would be available from regulatory submissions.
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| References | |
| Additional Infomation |
Tigozertinib is a fourth-generation, orally bioavailable, mutation-selective epidermal growth factor receptor (EGFR) inhibitor with potential antitumor activity. After oral administration, Tigozertinib targets and binds to EGFR carrying C797S triple mutations (including ex19del/T790M/C797S and L858R/T790M/C797S), thereby inhibiting its activity and blocking EGFR-mediated signaling. This may induce EGFR-overexpressing tumor cell death and inhibit tumor growth. EGFR is a receptor tyrosine kinase that is mutated in various tumor cell types and plays a crucial role in tumor cell proliferation and tumor angiogenesis. BLU-945 inhibits EGFR mutants carrying the C797S mutation, which cannot form covalent bonds with third-generation EGFR inhibitors, leading to resistance. Compared with other EGFR tyrosine kinase inhibitors, BLU-945 may have enhanced antitumor activity against tumors with C797S-mediated resistance.
BLU-945 (Tigozertinib) is a fourth-generation, reversible, mutant-selective EGFR inhibitor targeting T790M and C797S resistance mutations with IC50 <1 nM. It shows intracranial activity and is in phase 1/2 clinical trials for treatment-resistant EGFR-driven NSCLC. BLU-945 spares wild-type EGFR, reducing on-target toxicities. It is an investigational drug being developed to overcome resistance to third-generation EGFR inhibitors. |
| 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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