ML385 inihbits the activity of the Nrf2 transcription factor by binding to Neh1, a CNC-bZIP domain that allows Nrf2 to heterodimerize with small Maf proteins, blocking NRF2 transcriptional activity. Much research has been done on activating Nrf2 because it induces cytoprotective antioxidant genes. However, some cancer cells may use Nrf2 similarly for their survival. Nrf2 is overexpressed in certain cancers such as non-small cell lung cancer (NSCLC) often due to loss of function mutations in KEAP1, which targets Nrf2 for proteasomal degradation. ML385 was found to have anti-tumor activity with specificity and selectivity for NSCLC cells with KEAP1 mutations.
Front Oncol. 2021 May 26;11:679816.
Pharmacol Res Perspect. 2021 May;9(3):e00791.
Biomed Res Int. 2021 Jun 10;2021:6616547.
|Source||Front Oncol (2021). Figure 4. ML-385 (Abmole Bioscience, Houston, TX, USA)|
|Method||Cell Migration and Cell Invasion Assays|
|Cell Lines||Murine BC cell line 4T1 cells|
|Concentrations||0, 5, 10 µM|
|Results||We found that ML-385 treatment significantly attenuated NRF2, p-NRF2 expression (Figure 4A) and NRF2-responsive gene levels (Figure 4B) in DPP-4i-treated BC cells. Notably, DPP-4i-driven BC cell migration and invasion were significantly abrogated by ML-385 treatment with a dose-dependent manner (Figures 4C, D). Furthermore, DPP-4i–driven metastasis-associated gene levels were significantly attenuated after ML-385 treatment in BC cells (Figure 4E). These data indicate that NRF2 inhibition reverses DPP-4i–driven BC metastases in vitro.|
|Body Surface Area (m2)||0.007||0.025||0.15||0.05||0.02||0.5|
|Animal A (mg/kg) = Animal B (mg/kg) multiplied by||Animal B Km|
|Animal A Km|
For example, to modify the dose of Compound A used for a mouse (20 mg/kg) to a dose based on the BSA for a rat, multiply 20 mg/kg by the Km factor for a mouse and then divide by the Km factor for a rat. This calculation results in a rat equivalent dose for Compound A of 10 mg/kg.
|Solubility||DMSO: ≥ 30 mg/mL|
Small Molecule Inhibitor of NRF2 Selectively Intervenes Therapeutic Resistance in KEAP1-Deficient NSCLC Tumors
Anju Singh, et al. ACS Chem Biol. 2016 Nov 18;11(11):3214-3225. PMID: 27552339.
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