JBJ-04-125-02
目录号 : GC62632
JBJ-04-125-02 是一种有效的，选择性突变，变构和口服活性的 EGFR 抑制剂，对 EGFRL858R/T790M 的 IC50 为 0.26 nM。JBJ-04-125-02 可抑制癌细胞增殖和 EGFRL858R/T790M/C797S 信号传导。JBJ-04-125-02 具有抗肿瘤活性。
Cas No.:2060610-53-7
Sample solution is provided at 25 µL, 10mM.
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Quality Control & SDS
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- Purity: >98.00%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet
JBJ-04-125-02 is a potent, mutant-selective, allosteric and orally active 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[1].
JBJ-04-125-02 (0-1000 nM; 72 hours; H1975 cells) treatment could inhibit cell proliferation of H1975 cells at low nanomolar concentrations[1].JBJ-04-125-02 treatment also inhibits cell proliferation in Ba/F3 cells stably transfected with EGFRL858R, EGFRL858R/T790M, or EGFRL858R/T790M/C797S mutations[1].The ability of JBJ-04-125-02 (0.01-10 μM) to inhibit EGFR phosphorylation using Ba/F3, H1975 and NIH-3T3 cells is examined. JBJ-04-125-02 demonstrates mutant selectivity by inhibiting mutant EGFR and downstream AKT and ERK1/2 phosphorylation[1].
JBJ-04-125-02 (50 mg/kg; oral gavage; once daily; for 15 weeks; EGFRL858R/T790M/C797S genetically engineered mice) treatment leads to marked tumor regressions within 4 weeks of treatment[1].JBJ-04-125-02 exhibits a moderate half-life of 3 hours and a high area under curve of 728,577 min•ng/mL (AUClast) following 3 mg/kg intravenous (i.v.) dose. A 20 mg/kg oral dose of JBJ-04-125-02 achieves an average maximal plasma concentration of 1.1 μmol/L with an oral bioavailability of 3%[1].
[1]. To C, et al. Single and Dual Targeting of Mutant EGFR with an Allosteric Inhibitor. Cancer Discov. 2019 Jul;9(7):926-943.
| Cas No. | 2060610-53-7 | SDF | |
| 分子式 | C29H26FN5O3S | 分子量 | 543.61 |
| 溶解度 | 储存条件 | Store at -20°C | |
| General tips | 请根据产品在不同溶剂中的溶解度选择合适的溶剂配制储备液；一旦配成溶液，请分装保存，避免反复冻融造成的产品失效。 储备液的保存方式和期限：-80°C 储存时，请在 6 个月内使用，-20°C 储存时，请在 1 个月内使用。 为了提高溶解度，请将管子加热至37℃，然后在超声波浴中震荡一段时间。 |
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| Shipping Condition | 评估样品解决方案：配备蓝冰进行发货。所有其他可用尺寸：配备RT，或根据请求配备蓝冰。 | ||
| 制备储备液 | |||
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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 | 0.184 mL | 0.9198 mL | 1.8396 mL |
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动物平均体重 | g | |
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动物数量 | 只 |
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2.
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Single and Dual Targeting of Mutant EGFR with an Allosteric Inhibitor
Cancer Discov 2019 Jul;9(7):926-943.PMID:31092401DOI:10.1158/2159-8290.CD-18-0903.
Allosteric kinase inhibitors offer a potentially complementary therapeutic strategy to ATP-competitive kinase inhibitors due to their distinct sites of target binding. In this study, we identify and study a mutant-selective EGFR allosteric inhibitor, JBJ-04-125-02, which as a single agent can inhibit cell proliferation and EGFRL858R/T790M/C797S signaling in vitro and in vivo. However, increased EGFR dimer formation limits treatment efficacy and leads to drug resistance. Remarkably, osimertinib, an ATP-competitive covalent EGFR inhibitor, uniquely and significantly enhances the binding of JBJ-04-125-02 for mutant EGFR. The combination of osimertinib and JBJ-04-125-02 results in an increase in apoptosis, a more effective inhibition of cellular growth, and an increased efficacy in vitro and in vivo compared with either single agent alone. Collectively, our findings suggest that the combination of a covalent mutant-selective ATP-competitive inhibitor and an allosteric EGFR inhibitor may be an effective therapeutic approach for patients with EGFR-mutant lung cancer. SIGNIFICANCE: The clinical efficacy of EGFR tyrosine kinase inhibitors (TKI) in EGFR-mutant lung cancer is limited by acquired drug resistance, thus highlighting the need for alternative strategies to inhibit EGFR. Here, we identify a mutant EGFR allosteric inhibitor that is effective as a single agent and in combination with the EGFR TKI osimertinib.This article is highlighted in the In This Issue feature, p. 813.
Insights into the negative regulation of EGFR upon the binding of an allosteric inhibitor
Chem Biol Drug Des 2022 Apr;99(4):650-661.PMID:35152550DOI:10.1111/cbdd.14033.
Epidermal growth factor receptor (EGFR) is an intensively focused drug target for non-small cell lung cancer (NSCLC). JBJ-04-125-02 is an effective ATP-noncompetitive and T790M/L858R-selective inhibitor of EGFR, but the implied negative regulation mechanism is not fully clarified. Here, computational approaches were employed to address this. We find that JBJ-04-125-02 induces contrary effects on the binding of adenosine and phosphate moieties of ATP. The allosteric inhibitor lowers the stability of the hinge region, affecting the anchor of the adenosine portion of ATP, while a more closed conformation of P-loop is observed and might be unfavorable for the phosphotransfer and product release. The umbrella sampling simulations further demonstrate that less free energy is needed for the initial dissociation of ATP (the adenosine group) from the inactive EGFR in the presence of JBJ-04-125-02, but more for the phosphate groups egressing from the active cavity. Together, these findings provide a deeper understanding of the negative regulation of JBJ-04-125-02. Moreover, the key inter-molecular interactions contributing to ATP binding are identified. Our work might pave the way for designing allosteric drugs targeting EGFR for lung cancer patients, and also suggests that computational techniques are effective for investigating the allosteric mechanism.
Deciphering the T790M/L858R-Selective Inhibition Mechanism of an Allosteric Inhibitor of EGFR: Insights from Molecular Simulations
ACS Chem Neurosci 2021 Feb 3;12(3):462-472.PMID:33435671DOI:10.1021/acschemneuro.0c00633.
Allosteric inhibitors have lately received great attention because of their unique advantages, representing a more suitable choice for combinatory therapeutics targeting resistance-relevant signaling cascades. Among the various inhibitors, an allosteric small-molecule inhibitor, JBJ-04-125-02, has been proven to be effective against EGFRT790M/L858R mutant in vivo and in vitro. Herein, an in silico approach was adopted to shed light on the deep understanding of the higher selectivity of JBJ-04-125-02 against EGFRT790M/L858R mutant than wild-type EGFR. Our results indicate that JBJ-04-125-02 prefers to bind with the EGFRT790M/L858R mutant, stabilizes the inactive conformation, and further allosterically affects the conformations and dynamics of the interlobe cleft, including both the allosteric site and the ATP-binding site. Furthermore, docking results confirm that the binding of JBJ-04-125-02 at the allosteric site decreases the binding affinity of ANP (an ATP analogue) at the orthosteric site, especially for the Mut-holo one, which might further inhibit the function of EGFR. The present work provides a clear picture of the mutant-selective inhibition mechanism of an allosteric inhibitor of EGFR. The findings might pave the way for designing allosteric drugs targeting EGFR mutant lung cancer patients, which also takes a step forward in terms of drug resistance caused by protein mutations.
Molecular basis for cooperative binding and synergy of ATP-site and allosteric EGFR inhibitors
Nat Commun 2022 May 9;13(1):2530.PMID:35534503DOI:10.1038/s41467-022-30258-y.
Lung cancer is frequently caused by activating mutations in the epidermal growth factor receptor (EGFR). Allosteric EGFR inhibitors offer promise as the next generation of therapeutics, as they are unaffected by common ATP-site resistance mutations and synergize with the drug osimertinib. Here, we examine combinations of ATP-competitive and allosteric inhibitors to better understand the molecular basis for synergy. We identify a subset of irreversible EGFR inhibitors that display positive binding cooperativity and synergy with the allosteric inhibitor JBJ-04-125-02 in several EGFR variants. Structural analysis of these complexes reveals conformational changes occur mainly in the phosphate-binding loop (P-loop). Mutation of F723 in the P-loop reduces cooperative binding and synergy, supporting a mechanism in which F723-mediated contacts between the P-loop and the allosteric inhibitor are critical for synergy. These structural and mechanistic insights will aid in the identification and development of additional inhibitor combinations with potential clinical value.
Molecular mechanism study of EGFR allosteric inhibitors using molecular dynamics simulations and free energy calculations
J Biomol Struct Dyn 2022 Aug;40(13):5848-5857.PMID:33459177DOI:10.1080/07391102.2021.1874530.
ABTRACTThe epidermal growth factor receptor (EGFR) kinase inhibitors Gefitinib, Erlotinib, Afatinib and Osimertinib have been approved for the treatments of non-small cell lung cancer patients harboring sensitive EGFR mutations, but resistance arises rapidly. To date all approved EGFR inhibitors are ATP-competitive inhibitors, highlighting the need for therapeutic agents with alternative mechanisms of action. Allosteric kinase inhibitors offer a promising new therapeutic strategy to ATP-competitive inhibitors. The mutant-selective allosteric EGFR inhibitors EAI045 exhibited higher potency for EGFRL858R&T790M compared to WT, which was also effective in EGFR-mutant models including those harboring the C797S mutation. However, it was not effective as a single-agent inhibitor, and require the co-administration of the anti-EGFR antibody Cetuximab. Further efforts produced a more potent analog JBJ-04-125-02, which can inhibit cell proliferation as a single-agent inhibitor. In the present study, molecular dynamics simulations and free energy calculations were performed and revealed the detailed inhibitory mechanism of JBJ-04-125-02 as more potent EGFR inhibitor. Moreover, the energy difference between HOMO and LUMO calculated by DFT implied the higher interaction of JBJ-04-125-02 than EAI045 in the active site of the EGFR. The identified key features obtained from the molecular modeling enabled us to design novel EGFR allosteric inhibitors.Communicated by Ramaswamy H. Sarma.