SMER 28

IC50: N/A

SMER 28 is a new small-molecule enhancer of the cytostatic effects. The target of rapamycin proteins has been reported to be able to regulate various cellular processes including autophagy, which may play a protective role in some neurodegenerative and infectious diseases.

In vitro: SMER 28 independently induced autophagy of rapamycin in mammalian cells, enhancing the clearance of autophagy substrates such as A53T a-synuclein and mutant huntingtin, which were associated with Huntington’s and Parkinson’s disease. SMER 28, which seemed to act either independently or downstream of the rapamycin target, was found to attenuate the mutant huntingtin-fragment toxicity in Huntington’s disease cells [1].

In vivo: Previous study confirmed that the reduction of EGFP-HDQ74 aggregation occured through autophagy using autophagy-competent mouse embryonic fibroblasts (MEFs) (Atg5+/+). EGFP-HDQ74 aggregation was increased significantly in untreated Atg5-/- (autophagy-deficient) cells when compared with untreated Atg5+/+ cells. SMER 28 reduced EGFP-HDQ74 aggregation in Atg5+/+ cells significantly, but not in Atg5-/- cells). Therefore, SMER 28 could only reduce mutant huntingtin aggregation in autophagy-competent cells [1].

Clinical trial: N/A

Reference:
[1] Sarkar S,Perlstein EO,Imarisio S,Pineau S,Cordenier A,Maglathlin RL,Webster JA,Lewis TA,O'Kane CJ,Schreiber SL,Rubinsztein DC.  Small molecules enhance autophagy and reduce toxicity in Huntington's disease models. Nat Chem Biol.2007 Jun;3(6):331-8.

Pharmacological Reprogramming of Fibroblasts into Neural Stem Cells by Signaling-Directed Transcriptional Activation.[Pubmed:27133794]

Cell Stem Cell. 2016 May 5;18(5):653-67.

Cellular reprogramming using chemically defined conditions, without genetic manipulation, is a promising approach for generating clinically relevant cell types for regenerative medicine and drug discovery. However, small-molecule approaches for inducing lineage-specific stem cells from somatic cells across lineage boundaries have been challenging. Here, we report highly efficient reprogramming of mouse fibroblasts into induced neural stem cell-like cells (ciNSLCs) using a cocktail of nine components (M9). The resulting ciNSLCs closely resemble primary neural stem cells molecularly and functionally. Transcriptome analysis revealed that M9 induces a gradual and specific conversion of fibroblasts toward a neural fate. During reprogramming specific transcription factors such as Elk1 and Gli2 that are downstream of M9-induced signaling pathways bind and activate endogenous master neural genes to specify neural identity. Our study provides an effective chemical approach for generating neural stem cells from mouse fibroblasts and reveals mechanistic insights into underlying reprogramming processes.

Chemical inducers of autophagy that enhance the clearance of mutant proteins in neurodegenerative diseases.[Pubmed:20147746]

J Biol Chem. 2010 Apr 9;285(15):11061-7.

Many of the neurodegenerative diseases that afflict people are caused by intracytoplasmic aggregate-prone proteins. These include Parkinson disease, tauopathies, and polyglutamine expansion diseases such as Huntington disease. In Mendelian forms of these diseases, the mutations generally confer toxic novel functions on the relevant proteins. Thus, one potential strategy for dealing with these mutant proteins is to enhance their degradation. This can be achieved by up-regulating macroautophagy, which we will henceforth call autophagy. In this minireview, we will consider the reasons why autophagy up-regulation may be a powerful strategy for these diseases. In addition, we will consider some of the drugs and associated signaling pathways that can be used to induce autophagy with these therapeutic aims in mind.

Small molecules enhance autophagy and reduce toxicity in Huntington's disease models.[Pubmed:17486044]

Nat Chem Biol. 2007 Jun;3(6):331-8.

The target of rapamycin proteins regulate various cellular processes including autophagy, which may play a protective role in certain neurodegenerative and infectious diseases. Here we show that a primary small-molecule screen in yeast yields novel small-molecule modulators of mammalian autophagy. We first identified new small-molecule enhancers (SMER) and inhibitors (SMIR) of the cytostatic effects of rapamycin in Saccharomyces cerevisiae. Three SMERs induced autophagy independently of rapamycin in mammalian cells, enhancing the clearance of autophagy substrates such as mutant huntingtin and A53T alpha-synuclein, which are associated with Huntington's disease and familial Parkinson's disease, respectively. These SMERs, which seem to act either independently or downstream of the target of rapamycin, attenuated mutant huntingtin-fragment toxicity in Huntington's disease cell and Drosophila melanogaster models, which suggests therapeutic potential. We also screened structural analogs of these SMERs and identified additional candidate drugs that enhanced autophagy substrate clearance. Thus, we have demonstrated proof of principle for a new approach for discovery of small-molecule modulators of mammalian autophagy.

SMER28 is a positive regulator of autophagy acting via an mTOR-independent mechanism. SMER28 prevents the accumulation of amyloid beta peptide.

SMER 28,307538-42-7,Natural Products,Autophagy, buy SMER 28 , SMER 28 supplier , purchase SMER 28 , SMER 28 cost , SMER 28 manufacturer , order SMER 28 , high purity SMER 28