Key result
Compound 27b, a novel indirect AMPK activator, demonstrated potent tumor growth inhibition of 83% at 1 mg/kg twice daily in a human breast cancer xenograft mouse model.
Why the study?
Back-up medicinal chemistry research was performed on ASP4132, a clinical development compound and indirect AMPK activator, to identify novel activators with improved properties.
Effect estimate: 83% TGI
p-value: p=<0.001
Compound 27b was identified as a second-generation AMPK activator with improved aqueous solubility and reduced hERG inhibitory activity, representing a promising clinical candidate for cancer treatment.
Hypothesis-generating for AMPK activators in oncology; leaves open translation to human cardiovascular applications.
This study reports the synthesis and evaluation of novel indirect AMP-activated protein kinase (AMPK) activators. The series of compounds selectively inhibited cell growth in several human breast cancer cell lines by activating AMPK. We performed back-up medicinal chemistry synthetic research on ASP4132, a previously reported as a compound for clinical development that acts as an indirect AMPK activator. This led to the successful identification of 4-({4-[5-({1-[(5-ethoxypyrazin-2-yl)methyl]-4-fluoropiperidin-4-yl}methoxy)-3-methylpyridine-2-carbonyl]piperazin-1-yl}methyl)benzonitrile succinate (27b), a potent, highly aqueous soluble and metabolically stable compound in human hepatocytes. Compound 27b also showed weaker human Ether-a-go-go Related Gene (hERG) inhibitory activity than that of compound 13 and ASP4132. Therefore, 27b was a promising AMPK activator and a second-generation clinical candidate for treatment for human cancer.
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Kuramoto et al. (2020) studied Human breast cancer. Compound 27b vs. Vehicle was evaluated on Tumor growth inhibition (TGI) rate (83% TGI, p=<0.001). Compound 27b, a novel indirect AMPK activator, demonstrated potent tumor growth inhibition of 83% at 1 mg/kg twice daily in a human breast cancer xenograft mouse model.
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