CMS121 powder (1353224-53-9)

CMS121 powder is a substituted quinoline that has neuroprotective, anti-inflammatory, antioxidative, and renoprotective activities. It maintains glutathione (GSH) levels in HT22 mouse hippocampal cells in vitro in the presence of glutamate, induces differentiation of PC12 cells, prevents LPS-induced N9 microglial activation by 82% in N9 microglia, and scavenges free radicals in a Trolox equivalent activity concentration (TEAC) assay. CMS121 protects against ischemia and oxytosis in phenotypic screens in HT22 cells in vitro with EC50 values of 7 and 200 nM for preventing iodoacetic acid- or glutamate-induced cell death, respectively. It is also renoprotective, decreasing kidney weight loss and decreasing the expression of TNF-α, caspase-1, and inducible nitric oxide synthase (iNOS) in a SAMP8 mouse model of chronic kidney disease associated with rapid aging when administered at a dose of 10 mg/kg per day starting at nine months of age.

The team led by Salk Senior Staff Scientist Pamela Maher initially looked at two plant compounds with known medicinal properties: fisetin, a naturally occurring flavonoid found in fruits such as strawberries, and curcumin, an active compound found in the spice turmeric. These compounds are thought to have neuroprotective properties, allowing them to protect the neurons from some of the detrimental effects of aging.

The researchers are working to progress the fisetin derivative CMS121 and the curcumin derivative J147 into human trials. CMS121 has recently received National Institutes of Health funding for IND studies, while an IND requesting approval to start clinical trials with J147 in Alzheimer’s disease, is under FDA review. J147 is the best-studied curcumin derivative, the researchers pointed out, and has been shown to be effective in over a dozen rodent models of neurodegenerative diseases and memory enhancement. CMS121 has the same GNP properties as its native fisetin, but a much higher level of potency.

By using these compounds as a basis, the researchers created three Alzheimer’s drug candidates called CMS121, CAD31, and J147; they also used fisetin and curcumin directly. The team demonstrated that all five of these compounds reduced biomarkers of aging, increased the median lifespan of mice and flies, and reduced the signs of dementia.

CMS-121 (CMS121) is a novel and potent fisetin-based derivative with anti-aging, neuroprotective, anti-inflammatory, antioxidative, and renoprotective activities. According to the  the lab showed that these three synthetic candidates (known as CMS121, CAD31 and J147), as well as fisetin and curcumin, reduced the molecular markers of aging, as well as dementia, and extended the median lifespan of mice or flies.

Importantly, the molecular pathways engaged by these AD drug (inclouding the CMS121) candidates are the same as two other well-researched synthetic compounds that are known to extend the lifespan of many animals.  In additon, The fisetin derivative, CMS121, is currently in the animal toxicology studiesrequired for FDA approval to start clinical trials.

The next step for the research team involves moving the newly created compounds into human clinical trials. CMS121, which is based on fisetin, is currently in the animal toxicology study phase before it progresses into human clinical trials. The researchers did not mention the progress of the curcumin-basedCAD31, but J147, which is also based on curcumin, is currently undergoing review before it potentially advances to human trials early in 2019. The researchers also plan to include various biomarkers of aging in these human trials to ascertain any geroprotective effects they might have in people.

COA

1. Chiruta, C., Schubert, D., Dargusch, R., et al. Chemical modification of the multi-target neuroprotective compound fisetin J. Med. Chem. 55(1), 378-389 (2012).
2. Prior, M., Chiruta, C., Currais, A., et al. Back to the future with phenotypic screening ACS Chem Neurosci. 5(7), 503-513 (2014).
3. Currais, A., Maher, P., Schubert, D., et al. Prevention and treatment of aging and neurodegenerative diseases (2017).