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MTOR-independent activator of TFEB for autophagy enhancement and uses thereof

A free and neurodegenerative technology, applied in the direction of active ingredients of ketones, nervous system diseases, drug combinations, etc., can solve the problems of poor blood-brain barrier penetration and achieve the elimination of MTOR-related complications, wide application fields, The effect of simple chemical structure

Inactive Publication Date: 2016-11-09
HONG KONG BAPTIST UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

However, trehalose and sucrose do not penetrate the blood-brain barrier (BBB) ​​well

Method used

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  • MTOR-independent activator of TFEB for autophagy enhancement and uses thereof
  • MTOR-independent activator of TFEB for autophagy enhancement and uses thereof
  • MTOR-independent activator of TFEB for autophagy enhancement and uses thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment

[0092] In the following examples, the following materials were used; various commercial sources of the materials are provided. Details of the various schemes are also set forth below:

[0093] Reagents and Antibodies

[0094]Test samples of monocarbonyl analogues of curcumin were kindly provided by Dr. Bo Zhou (Lanzhou University, China). Compound C1 ((1E,4E)-1,5-bis(2-methoxy-phenyl)pent-1,4-dien-3-one) was synthesized from 2-methoxybenzene in a single-step reaction Synthetic formaldehyde. The structure and purity of the compound were confirmed by 1H NMR and HPLC. Curcumin (08511), chloroquine (C6628), doxycycline (D9891), and anti-Flag M2 antibody (F1804) were purchased from Sigma-Aldrich. Torin1(2273-5) was purchased from BioVision Company. Anti-phospho-AKT (ser473) antibody (9271), anti-AKT antibody (9272), anti-phospho-MTOR (Ser2448) antibody (2971), anti-MTOR antibody (2983), anti-phospho-P70S6K / RPS6KB1 (Thr389) antibody (9234 ), anti-P70S6K / RPS6KB1 antibody (9202)...

Embodiment I

[0115] Novel autophagy enhancers identified from monocarbonyl analogs of curcumin.

[0116] First, the inventors of the present application measured by LDH ( figure 1 B) tested the test compound (such as figure 1 Shown in A) Cytotoxicity at 1 μM and 10 μM over 24 hours and subsequently using a concentration of 1 μM. Compared with vehicle control (0.1% DMSO), curcumin (10 μM) and analogs A2, B3 and C1 (1 μM) significantly increased the level of microtubule-associated protein 1 light chain 3B (LC3B)-II in N2a cells ( figure 2 A). In the presence of the lysosomal inhibitor chloroquine (CQ), these analogs further increased LC3-II levels compared to CQ treatment alone ( figure 2 B). Furthermore, when the expression of autophagy-related gene 5 (Atg5) was interfered with by siRNA, these compounds could not increase the level of LC3-II ( figure 2 C). The data indicate that curcumin analogs A2, B3 and C1 enhance autophagy rather than prevent lysosomal degradation.

Embodiment II

[0118] Effects of curcumin analogues on the MTOR pathway

[0119] Since curcumin enhances autophagy via inhibition of the MTOR pathway, the effects of the three newly identified autophagy enhancers of the present invention on the MTOR pathway were confirmed. Similar to curcumin, A2 and B3 inhibited the phosphorylation of RPS6KB1 / p70S6K, MTOR and AKT ( image 3 A and image 3 B). Torin1, a potent MTOR inhibitor, was used as a positive control. C1 significantly promoted the phosphorylation of RPS6KB1, MTOR and AKT ( image 3 A and image 3 B).

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Abstract

A composition comprising an autophagy enhancement compound is disclosed. Small molecules that are able to enhance autophagy and lysosome biogenesis by activating the gene TFEB which can prevent the accumulation of toxic protein aggregates in treating neurodegenerative diseases are disclosed.

Description

[0001] Cross References to Related Applications [0002] This application claims the benefit of U.S. Provisional Patent Application Serial No. 61 / 949,233, filed March 06, 2014, and U.S. Nonprovisional Patent Application Serial No. 14 / 609,438, filed January 30, 2015, the disclosures of which are hereby Incorporated herein by reference. technical field [0003] The present invention relates to a composition comprising an autophagy enhancing compound. Specifically, the present invention relates to a composition comprising small molecules capable of enhancing autophagy and lysosomal biogenesis by activating the gene TFEB, which can prevent the accumulation of toxic protein aggregates for therapeutic Neurodegenerative diseases such as Parkinson's disease, Alzheimer's disease and Huntington's disease. Background technique [0004] Macroautophagy, referred to herein as autophagy, is a highly conserved process for cellular degradation and recycling of cytoplasmic contents to maint...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/12
CPCA61K31/12A61P25/00A61P25/16A61P25/28
Inventor 李敏宋聚先曾玉刘亮锋
Owner HONG KONG BAPTIST UNIV
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