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JBJ-04-125-02 R-isomer, the R-enantiomer of JBJ-04-125-02, is a novel, highly potent, mutant-specific, allosteric and orally bioavailable EGFR inhibitor with an IC50 of 0.26 nM for EGFRL858R/T790M. JBJ-04-125-02 can inhibit cancer cell proliferation and EGFRL858R/T790M/C797S signaling. JBJ-04-125-02 has anti-tumor activities.
| Targets |
EGFR(L858R/T790M)
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|---|---|
| ln Vitro |
H1975 cells treated with JBJ-04-125-02 (0-1000 nM; 72 hours) exhibit reduced cell growth at low nanomolar concentrations [1]. In Ba/F3 cells that have been transfected with EGFRL858R, EGFRL858R/T790M, or EGFRL858R/T790M/C797S mutations, JBJ-04-125-02 therapy also suppresses cell proliferation [1]. In Ba/F3, H1975, and NIH-3T3 cells, the inhibitory effect of JBJ-04-125-02 (0.01-10 μM) on EGFR phosphorylation was investigated. JBJ-04-125-02 inhibited downstream phosphorylation of AKT and ERK1/2 and mutant EGFR, demonstrating mutant selectivity [1].
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| ln Vivo |
Significant tumor regression was observed within 4 weeks of treatment with JBJ-04-125-02 (50 mg/kg; oral gavage; once daily; for 15 weeks; EGFRL858R/T790M/C797S genetically modified mice) [1]. After receiving a 3 mg/kg intravenous (IV) dose, JBJ-04-125-02 displays a high area under the curve (728,577 min·ng/mL) and a moderate half-life of 3 hours. The average maximum plasma concentration is 1.1 μmol/L and the oral bioavailability is 3% when JBJ-04-125-02 is administered orally at a dose of 20 mg/kg [1].
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| Enzyme Assay |
Biochemical assays with L858R/T790M EGFR were carried out using a homogeneous time-resolved fluorescence (HTRF) KinEASE-TK (Cisbio) assay as described previously at the ICCB Longwood Screening Facility at Harvard Medical School. Assays were performed with enzyme concentration of 20pM and 100µM ATP. Inhibitor compounds in DMSO were dispensed directly into 384-well plates with the D300 Digital dispenser (Hewlett Packard) followed immediately by the addition of aqueous buffered solutions using the Multidrop Combi Reagent Dispenser (Thermo Fisher). IC50 values were determined with 11- or 23-point inhibition curves in triplicate.[1]
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| Cell Assay |
Cell Proliferation Assay[1]
Cell Types: H1975 Cell Tested Concentrations: 0 nM, 0.1 nM, 1 nM, 10 nM, 100 nM, 1000 nM Incubation Duration: 72 hrs (hours) Experimental Results: Low nanomolar concentrations inhibited cell proliferation of H1975 cells. |
| Animal Protocol |
Animal/Disease Models: EGFRL858R/T790M/C797S genetically engineered mice (GEM) [1]
Doses: 50 mg/kg Route of Administration: po (oral gavage); one time/day; lasted for 15 weeks. Experimental Results: Tumors were Dramatically diminished within 4 weeks of treatment. |
| References |
[1]. To C, et al. Single and Dual Targeting of Mutant EGFR with an Allosteric Inhibitor. Cancer Discov. 2019 Jul;9(7):926-943.
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| Additional Infomation |
In summary, we identify a single agent mutant-selective allosteric EGFR inhibitor, JBJ-04-125-02. Although effective in vitro and in vivo, there are still limitations to this approach. The identification of JBJ-04-125-02 serves as an important proof of concept to demonstrate the feasibility of developing a single agent mutant selective allosteric EGFR inhibitor. Current efforts should focus on developing an allosteric inhibitor that can ideally target not only L858R but also Del_19 mutation; however, since the allosteric pocket in which JBJ-04-125-02 and previous allosteric inhibitors bind is uniquely formed in the presence of the L858R mutation, it remains a challenge to develop an allosteric inhibitor that could simultaneously inhibit both mutant forms of EGFR. Intriguingly, although osimertinib is more effective than gefitinib or erlotinib in EGFR TKI naïve patients, it is disproportionally more effective in patients with EGFR exon 19 deletions (median PFS 21.4 vs. 11.0 months) compared to those with an L858R mutation (median PFS 14.4 vs. 9.5 months), suggesting a need to continue to develop new therapeutic approaches specifically for patients with EGFR L858R mutant NSCLC. The greatest therapeutic potential of JBJ-04-125-02 is observed when it is combined with osimertinib, and as such, the two-drug combination could potentially lead to enhanced clinical benefits beyond those currently achievable with single agent osimertinib in patients with EGFR L858R mutant lung cancer.[1]
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| Molecular Formula |
C29H26FN5O3S
|
|---|---|
| Molecular Weight |
543.6118
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| Exact Mass |
543.17
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| Elemental Analysis |
C, 64.07; H, 4.82; F, 3.49; N, 12.88; O, 8.83; S, 5.90
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| CAS # |
2060610-53-7
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| Related CAS # |
(Rac)-JBJ-04-125-02;2140807-05-0
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| PubChem CID |
124173751
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| Appearance |
Typically exists as solid at room temperature
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| LogP |
3.8
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| Hydrogen Bond Donor Count |
3
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| Hydrogen Bond Acceptor Count |
8
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| Rotatable Bond Count |
6
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| Heavy Atom Count |
39
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| Complexity |
870
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| Defined Atom Stereocenter Count |
1
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| SMILES |
C1CN(CCN1)C2=CC=C(C=C2)C3=CC4=C(CN(C4=O)[C@H](C5=C(C=CC(=C5)F)O)C(=O)NC6=NC=CS6)C=C3
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| InChi Key |
VHQVOTINPRYDAO-AREMUKBSSA-N
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| InChi Code |
InChI=1S/C29H26FN5O3S/c30-21-5-8-25(36)24(16-21)26(27(37)33-29-32-11-14-39-29)35-17-20-2-1-19(15-23(20)28(35)38)18-3-6-22(7-4-18)34-12-9-31-10-13-34/h1-8,11,14-16,26,31,36H,9-10,12-13,17H2,(H,32,33,37)/t26-/m1/s1
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| Chemical Name |
(2R)-2-(5-fluoro-2-hydroxyphenyl)-2-[3-oxo-5-(4-piperazin-1-ylphenyl)-1H-isoindol-2-yl]-N-(1,3-thiazol-2-yl)acetamide
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| Synonyms |
JBJ-04-125-02; 2060610-53-7; (2R)-2-(5-fluoro-2-hydroxyphenyl)-2-{1-oxo-6-[4-(piperazin-1-yl)phenyl]-1,3-dihydro-2H-isoindol-2-yl}-N-(1,3-thiazol-2-yl)acetamide; (2R)-2-(5-fluoro-2-hydroxyphenyl)-2-[3-oxo-5-(4-piperazin-1-ylphenyl)-1H-isoindol-2-yl]-N-(1,3-thiazol-2-yl)acetamide; SCHEMBL18360815; GTPL12982; BCP32863; EX-A4047
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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) |
May dissolve in DMSO (in most cases), if not, try other solvents such as H2O, Ethanol, or DMF with a minute amount of products to avoid loss of samples
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|---|---|
| Solubility (In Vivo) |
Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.
Injection Formulations
Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)(e.g. IP/IV/IM/SC) *Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution. Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline) Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil) Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals). View More
Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)] Oral Formulations
Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium) Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals). View More
Oral Formulation 3: Dissolved in PEG400 (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 1.8396 mL | 9.1978 mL | 18.3955 mL | |
| 5 mM | 0.3679 mL | 1.8396 mL | 3.6791 mL | |
| 10 mM | 0.1840 mL | 0.9198 mL | 1.8396 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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