Spautin-1

Description:

IC50: 0.6 and 0.7 μM for USP10 and USP13 activity, respectively

Autophagy is an important intracellular catabolic mechanism which mediates the degradation of cytoplasmic proteins and organelles. USP10 mediates the deubiquitination of p53, regulating deubiquitination the activities of USP10 and USP13 by Beclin1 provides a mechanism for Beclin1 to control the levels of p53. Spautin-1 is a novel autophagy inhibitor.

In vitro: Spautin-1 promotes the degradation of Vps34 PI3 kinase complexes via inhibiting two ubiquitinspecific peptidases, USP10 and USP13, that target the Beclin1 subunit of Vps34 complexes. Spautin-1 had no effect on the growth and survival of Bcap-37 cells under normal culture conditions but dramatically enhanced cell death in glucose-free media. Under glucose-free conditions, western blotting for LC3 further confirmed that autophagy was induced, which was inhibited by spautin-1. Similar results were obtained with MCF-7 and BT549 cells. Therefore, spautin-1 can sensitize tumor cells to apoptosis under nutritional deprived conditions [1].

In vivo: So far, there is no report to investigate the in vivo animal efficacy of spautin-1.

Clinical trial: Up to now, spautin-1 is still in the preclinical development stage.

Reference:
[1] Liu J, Xia H, Kim M, Xu L, Li Y, Zhang L, Cai Y, Norberg HV, Zhang T, Furuya T, Jin M, Zhu Z, Wang H, Yu J, Li Y, Hao Y, Choi A, Ke H, Ma D, Yuan J.  Beclin1 controls the levels of p53 by regulating the deubiquitination activity of USP10 and USP13. Cell. 2011 Sep 30;147(1):223-34.


Spautin-1 Ameliorates Acute Pancreatitis via Inhibiting Impaired Autophagy and Alleviating Calcium Overload.[Pubmed:27579473]

Mol Med. 2016 Oct;22:643-652.

Acute pancreatitis is characterized by zymogen pre-activation. Severe inflammation caused by zymogen activation can eventually lead to multiple organ dysfunctions, which contributes to the high mortality rate of severe acute pancreatitis. However, there is no specific treatment available for acute pancreatitis therapy. Here, we show that Spautin-1, which effectively inhibits autophagy flux, ameliorated the pathogenesis of acute pancreatitis induced by cerulein or L-Arginine. CaMKII phosphorylation due to cytosolic calcium oeverload was revealed in this paper. It was also demonstrated that autophagic protein aggregates degradation blockade accompanying with impaired autophagy correlated positively to intra acinar cells digestive aymogen activation sitimulated by cerulein or L-Arginine. The role of Spautin-1 in ameliorating acute pancreatitis was shown here to be associated with impaired autophagy inhibition and Ca(2+) overload alleviation. We provided a promising therapy for acute pancreatitis here through targeting both impaired autophagy and increased cytosolic calcium.

Spautin-1, a novel autophagy inhibitor, enhances imatinib-induced apoptosis in chronic myeloid leukemia.[Pubmed:24585095]

Int J Oncol. 2014 May;44(5):1661-8.

Imatinib mesylate (IM), a targeted competitive inhibitor of the BCR-ABL tyrosine kinase, has revolutionized the clinical treatment of chronic myeloid leukemia (CML). However, resistance and intolerance are still a challenge in the treatment of CML. Autophagy has been proposed to play a role in IM resistance. To investigate the anti-leukemic activity of specific and potent autophagy inhibitor-1 (Spautin-1) in CML, we detected its synergistic effect with IM in K562 and CML cells. Our results showed that Spautin-1 markedly inhibited IM-induced autophagy in CML cells by downregulating Beclin-1. Spautin-1 enhanced IM-induced CML cell apoptosis by reducing the expression of the anti-apoptotic proteins Mcl-1 and Bcl-2. We further demonstrated that the pro-apoptotic activity of Spautin-1 was associated with activation of GSK3beta, an important downstream effector of PI3K/AKT. The findings indicate that the autophagy inhibitor Spautin-1 enhances IM-induced apoptosis by inactivating PI3K/AKT and activating downstream GSK3beta, leading to downregulation of Mcl-1 and Bcl-2, which represents a promising approach to improve the efficacy of IM in the treatment of patients with CML.

PDGF-mediated autophagy regulates vascular smooth muscle cell phenotype and resistance to oxidative stress.[Pubmed:23421427]

Biochem J. 2013 May 1;451(3):375-88.

Vascular injury and chronic arterial diseases result in exposure of VSMCs (vascular smooth muscle cells) to increased concentrations of growth factors. The mechanisms by which growth factors trigger VSMC phenotype transitions remain unclear. Because cellular reprogramming initiated by growth factors requires not only the induction of genes involved in cell proliferation, but also the removal of contractile proteins, we hypothesized that autophagy is an essential modulator of VSMC phenotype. Treatment of VSMCs with PDGF (platelet-derived growth factor)-BB resulted in decreased expression of the contractile phenotype markers calponin and alpha-smooth muscle actin and up-regulation of the synthetic phenotype markers osteopontin and vimentin. Autophagy, as assessed by LC3 (microtubule-associated protein light chain 3 alpha; also known as MAP1LC3A)-II abundance, LC3 puncta formation and electron microscopy, was activated by PDGF exposure. Inhibition of autophagy with 3-methyladenine, Spautin-1 or bafilomycin stabilized the contractile phenotype. In particular, Spautin-1 stabilized alpha-smooth muscle cell actin and calponin in PDGF-treated cells and prevented actin filament disorganization, diminished production of extracellular matrix, and abrogated VSMC hyperproliferation and migration. Treatment of cells with PDGF prevented protein damage and cell death caused by exposure to the lipid peroxidation product 4-hydroxynonenal. The results of the present study demonstrate a distinct form of autophagy induced by PDGF that is essential for attaining the synthetic phenotype and for survival under the conditions of high oxidative stress found to occur in vascular lesions.

Beclin1 controls the levels of p53 by regulating the deubiquitination activity of USP10 and USP13.[Pubmed:21962518]

Cell. 2011 Sep 30;147(1):223-34.

Autophagy is an important intracellular catabolic mechanism that mediates the degradation of cytoplasmic proteins and organelles. We report a potent small molecule inhibitor of autophagy named "Spautin-1" for specific and potent autophagy inhibitor-1. Spautin-1 promotes the degradation of Vps34 PI3 kinase complexes by inhibiting two ubiquitin-specific peptidases, USP10 and USP13, that target the Beclin1 subunit of Vps34 complexes. Beclin1 is a tumor suppressor and frequently monoallelically lost in human cancers. Interestingly, Beclin1 also controls the protein stabilities of USP10 and USP13 by regulating their deubiquitinating activities. Since USP10 mediates the deubiquitination of p53, regulating deubiquitination activity of USP10 and USP13 by Beclin1 provides a mechanism for Beclin1 to control the levels of p53. Our study provides a molecular mechanism involving protein deubiquitination that connects two important tumor suppressors, p53 and Beclin1, and a potent small molecule inhibitor of autophagy as a possible lead compound for developing anticancer drugs.

Spautin-1 is a specific and potent autophagy inhibitor which inhibits ubiquitin-specific peptidases, USP10 and USP13 with IC50s of 0.6-0.7 μM.

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