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Purity: =98.3%
Pralsetinib (GAVRETO; BLU667; BLU-667) is a novel, highly potent, selective, FDA approved RET inhibitor with anticancer activity. Its approval for the treatment of metastatic non-small cell lung cancer (NSCLC) exhibiting RET fusion was granted in 2020. At an IC50 of 0.3–0.4 nM, pralisetinib inhibits RET in WT RET, RET mutants V804L, V804M, M918T, and CCDC6-RET fusion. RET fusions, predicted resistant mutants, and mutations are all effectively and selectively inhibited by BLU-667. Lung and thyroid cancer are among the many malignancies that are primarily caused by RET fusions; our findings also indicate that certain colon and breast cancers are largely motivated by RET. Through concurrently focusing on the main driver and anticipated resistant mutations that make cancer cells immune to current, approved medication treatments. Pralsetinib (GAVRETO) was given accelerated approval by the Food and Drug Administration on September 4, 2020, for use in adult patients with metastatic RET fusion-positive non-small cell lung cancer (NSCLC) that was identified by an FDA-approved test.
| Targets |
RET (IC50 = 0.4 nM); RET V804L (IC50 = 0.3 nM); RET V804M (IC50 = 0.4 nM); RET M918T (IC50 = 0.4 nM); CCDC6-RET (IC50 = 0.4 nM)
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| ln Vitro |
BLU-667 is at least a hundred times more selective for RET than 96% of the kinases tested (371 kinases in total). BLU-667 selectively inhibits RET signaling in cancers with altered RET across various lineages. In comparison to multikinase inhibitors, BLU-667-mediated RET pathway inhibition also more effectively suppresses the proliferation of RET-modified cell lines[1].
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| ln Vivo |
BLU-667 effectively suppresses NSCLC and thyroid cancer xenograft growth in vivo when driven by different RET mutations and fusions, but does not inhibit VEGFR2. Throughout the in vivo trials, BLU-667 is well tolerated[1].
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| Enzyme Assay |
BLU-667 is tested for inhibitory activity against a panel of 371 kinases at 300 nmol/L. The 23 kinases that exhibit >50% inhibition at 300 nmol/L are chosen for complete 10-point concentration-response curves, utilizing BLU-667 (1 μmol/L maximum concentration) at 200 μmol/L ATP to produce biochemical IC50 (Reaction Biology Corp). The reaction is initiated with 33P-ATP (10 mCi/mL), and kinase activity is then detected through filter-binding methodology.
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| Cell Assay |
Following a 48-hour exposure to compound concentrations ranging from 25 µM to 95.4 pM, the proliferation of KIF5B-RET Ba/F3 cells is measured using Cell Titer Glo. BrdU incorporation is used to measure the proliferation of TT, MZ-CRC-1, TPC-1, or LC2/ad cells after four days of compound exposure.
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| Animal Protocol |
Mice: BALB/c nude mice are injected subcutaneously with TT cells, KIF5B-RET V804L Ba/F3 cells, or KIF5B-RET Ba/F3 cells into the right flank. Mice are given vehicle, 3 mg/kg, 10 mg/kg, or 30 mg/kg of Pralsetinib (Blu667) twice a day, or 60 mg/kg of XL184 or 60 mg/kg of Pralsetinib (Blu667; given orally) once a day for all experiments.
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| References | |
| Additional Infomation |
Pralsetinib is a Kinase Inhibitor. The mechanism of action of pralsetinib is as a Rearranged during Transfection (RET) Inhibitor.
See also: Pralsetinib (annotation moved to). |
| Molecular Formula |
C27H32FN9O2
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|---|---|
| Molecular Weight |
533.6005
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| Exact Mass |
533.27
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| Elemental Analysis |
C, 60.77; H, 6.04; F, 3.56; N, 23.62; O, 6.00
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| CAS # |
2097132-94-8
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| Related CAS # |
trans-Pralsetinib;2097132-93-7
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| PubChem CID |
129073603
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| Appearance |
White to off-white solid powder
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| LogP |
3.1
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| Hydrogen Bond Donor Count |
3
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| Hydrogen Bond Acceptor Count |
9
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| Rotatable Bond Count |
8
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| Heavy Atom Count |
39
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| Complexity |
816
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| Defined Atom Stereocenter Count |
1
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| SMILES |
CC1=CC(=NN1)NC2=NC(=NC(=C2)C)C3CCC(CC3)(C(=O)N[C@@H](C)C4=CN=C(C=C4)N5C=C(C=N5)F)OC
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| InChi Key |
GBLBJPZSROAGMF-SIYOEGHHSA-N
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| InChi Code |
InChI=1S/C27H32FN9O2/c1-16-11-22(33-23-12-17(2)35-36-23)34-25(31-16)19-7-9-27(39-4,10-8-19)26(38)32-18(3)20-5-6-24(29-13-20)37-15-21(28)14-30-37/h5-6,11-15,18-19H,7-10H2,1-4H3,(H,32,38)(H2,31,33,34,35,36)/t18-,19?,27?/m0/s1
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| Chemical Name |
N-[(1S)-1-[6-(4-fluoropyrazol-1-yl)pyridin-3-yl]ethyl]-1-methoxy-4-[4-methyl-6-[(5-methyl-1H-pyrazol-3-yl)amino]pyrimidin-2-yl]cyclohexane-1-carboxamide
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| Synonyms |
BLU-667; BLU 667; BLU667; Gavreto; Pralsetinib
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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 |
| 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 (~187.4 mM)
Water: <1 mg/mL Ethanol: ~13 mg/mL (~24.4 mM) |
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (4.69 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% 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 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: ≥ 2.5 mg/mL (4.69 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 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly. View More
Solubility in Formulation 3: ≥ 2.5 mg/mL (4.69 mM) (saturation unknown) in 5% DMSO + 40% PEG300 + 5% Tween80 + 50% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution. |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 1.8741 mL | 9.3703 mL | 18.7406 mL | |
| 5 mM | 0.3748 mL | 1.8741 mL | 3.7481 mL | |
| 10 mM | 0.1874 mL | 0.9370 mL | 1.8741 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.
| NCT Number | Recruitment | interventions | Conditions | Sponsor/Collaborators | Start Date | Phases |
| NCT03037385 | Active Recruiting |
Drug: pralsetinib (BLU-667) |
Neoplasms Lung Diseases |
Hoffmann-La Roche | March 17, 2017 | Phase 1 Phase 2 |
| NCT04760288 | Recruiting | Drug: Pralsetinib Drug: Cabozantinib |
Medullary Thyroid Cancer | Hoffmann-La Roche | October 30, 2023 | Phase 3 |
| NCT04222972 | Recruiting | Drug: Pralsetinib Drug: Carboplatin |
Lung Neoplasm Neoplasms |
Hoffmann-La Roche | July 24, 2020 | Phase 3 |
| NCT05170204 | Recruiting | Drug: Alectinib Drug: Pralsetinib |
Non-Small Cell Lung Cancer | Hoffmann-La Roche | November 1, 2022 | Phase 3 |
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