SMER28- Enhancer of Autophagy

SMER28 is a small-molecule enhancer (SMER) of autophagy that increases autophagosome synthesis and enhances clearance of aggregate-prone substrates, including those relevant to Huntington’s, Parkinson’s, and Alzheimer’s diseases.
 

It is a positive regulator of autophagy in a mechanism independent from the mTOR pathway. It increases autophagosome synthesis and enhances the clearance of model autophagy substrates such as A53T a-synuclein and mutant huntingtin fragments. A marked decrease in β/APP-CTF levels and enhancement for degradation of β/APP-CTF via autophagy is also induced by SMER28.
 

SMER28 is also a potential treatment for Diamond Blackfan Anemia (DBA) which is a rare, severe blood disorder in which the bone marrow cannot make enough oxygen-carrying red blood cells. When SMER28 was used to treat the marrow in zebrafish and mouse models of DBA, the animals made erythroid progenitor cells that in turn made red blood cells, reversing or stabilizing anemia. The same was true in cells from DBA patients transplanted into mice. The higher the dose of SMER28, the more red blood cells were produced, and no ill effects were found. SMER28 acts through autophagy factor ATG5 to stimulate erythropoiesis and upregulate expression of globin genes.
 

SMER28 has been shown to protect mouse bone marrow and liver against radiotherapy. SMER28 enhanced the autophagy flux and improved the survival of normal hepatocytes of mice. In vivo subcutaneous administration of SMER28 protected mouse liver and bone marrow against radiation damage and facilitated survival of mice after lethal whole body or abdominal irradiation. Effective cytoprotectors that are selective for normal tissues could decrease radiotherapy and chemotherapy sequelae and facilitate the safe administration of higher radiation doses. With further research, SMER28 could improve the cure rates of radiotherapy for cancer patients.
 

References

  • “Stem-Cell-Derived Cells Flag a Possible New Treatment for Rare Blood Disorder.” EurekAlert, American Association for the Advancement of Science, 8 Feb. 2017, www.eurekalert.org/pub_releases/2017-02/bch-scf020617.php.
  • Tian, Yuan, et al. “A Small-Molecule Enhancer of Autophagy Decreases Levels of Aβ and APP-CTF via Atg5-Dependent Autophagy Pathway.” The FASEB Journal, vol. 25, no. 6, June 2011, pp. 1934–1942., doi:10.1096/fj.10-175158.
  • Koukourakis, Michael I., et al. “SMER28 Is a MTOR-Independent Small Molecule Enhancer of Autophagy That Protects Mouse Bone Marrow and Liver against Radiotherapy.” Investigational New Drugs, vol. 36, no. 5, Oct. 2018, pp. 773–781., doi:10.1007/s10637-018-0566-0.

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