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.
Physicochemical Properties
| Molecular Formula | C28H37FN6O3S |
| Molecular Weight | 556.70 |
| Exact Mass | 556.26 |
| Elemental Analysis | C, 60.41; H, 6.70; F, 3.41; N, 15.10; O, 8.62; S, 5.76 |
| CAS # | 2660250-10-0 |
| PubChem CID | 156538665 |
| Appearance | Light yellow to yellow solid powder |
| LogP | 4.6 |
| Hydrogen Bond Donor Count | 1 |
| Hydrogen Bond Acceptor Count | 10 |
| Rotatable Bond Count | 8 |
| Heavy Atom Count | 39 |
| Complexity | 922 |
| Defined Atom Stereocenter Count | 4 |
| 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 |
| InChi Key | LIMFPAAAIVQRRD-BCGVJQADSA-N |
| 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 |
| 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 |
| Synonyms | BLU-945; BLU 945; BLU945; tigozertinib |
| HS Tariff Code | 2934.99.9001 |
| 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) |
Biological Activity
| 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]. |
| 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]. |
| 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 |
[1]. Inhibitors of mutant forms of egfr. Patent WO2021133809A1. [2]. BLU-945, a fourth-generation, potent and highly selective epidermal growth factor receptor tyrosine kinase inhibitor with intracranial activity, demonstrates robust in vivo anti-tumor activity in models of osimertinib-resistant non-small cell lung cancer. [3]. Discovery of BLU-945, a Reversible, Potent, and Wild-Type-Sparing Next-Generation EGFR Mutant Inhibitor for Treatment-Resistant Non-Small-Cell Lung Cancer. J Med Chem. 2022 Jul 28;65(14):9662-9677. [4]. A phase 1/2 study of BLU-945 in patients with common activating EGFRmutant non-small cell lung cancer (NSCLC) (SYMPHONY trial-in-progress). |
| 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. |
Solubility Data
| Solubility (In Vitro) | DMSO : ~100 mg/mL (~179.63 mM) |
| 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 |