Title:
MTOR INHIBITOR AND USE THEREOF
Document Type and Number:
WIPO Patent Application WO/2023/168771
Kind Code:
A1
Abstract:
The present invention relates to the field of biotechnology. Provided are an mTOR inhibitor and the use thereof. The mTOR inhibitor is obtained by means of mutating aspartic acids at positions 14, 17 and 18 in 30 amino acids at the C terminal of an ATP6AP1 protein into alanines, and the sequence of the 30 amino acids is as shown in SEQ ID NO: 1. By means of a new proximity labeling and screening method, a C-terminal fragment (C tail) of an ATP6AP1 protein is found as a guanylate exchange factor (GEF) of Rheb which can activate Rheb. On this basis, aspartic acids at positions 14, 17 and 18 in 30 amino acids at the C-terminal are all mutated into alanines, so as to obtain a new mTOR inhibitor. The mTOR inhibitor can bind to and block the inhibition of Rheb by means of endogenous ATP6AP1, thereby inhibiting the mTORC1 signaling pathway.
Inventors:
SONGYANG ZHOU (CN)
FENG RAN (CN)
LIU FENG (CN)
WU SU (CN)
ZHOU ZHIFEN (CN)
LI RUOFEI (CN)
FENG RAN (CN)
LIU FENG (CN)
WU SU (CN)
ZHOU ZHIFEN (CN)
LI RUOFEI (CN)
Application Number:
PCT/CN2022/084001
Publication Date:
September 14, 2023
Filing Date:
March 30, 2022
Export Citation:
Assignee:
UNIV SUN YAT SEN (CN)
International Classes:
C07K14/47; A61K38/17; A61P35/00; A61P39/06; C12N9/12; C12N15/62; C12N15/85; C12Q1/02; G01N33/68
Domestic Patent References:
| WO2008110491A2 | 2008-09-18 |
Foreign References:
| CN113271970A | 2021-08-17 | |||
| CN111568923A | 2020-08-25 | |||
| CN110051845A | 2019-07-26 | |||
| US20130252950A1 | 2013-09-26 |
Other References:
FELDMAN, M. E. ET AL.: "Active-Site Inhibitors of mTOR Target Rapamycin-Resistant Outputs of mTORC1 and mTORC2.", PLOS BIOLOGY, vol. 7, no. 2, 28 February 2009 (2009-02-28), XP008151030, DOI: 10.1371/journal.pbio.1000038
PAREJA FRESIA, BRANDES ALISSA H., BASILI THAIS, SELENICA PIER, GEYER FELIPE C., FAN DAN, DA CRUZ PAULA ARNAUD, KUMAR RAHUL, BROWN : "Loss-of-function mutations in ATP6AP1 and ATP6AP2 in granular cell tumors", NATURE COMMUNICATIONS, vol. 9, no. 1, 30 August 2018 (2018-08-30), pages 3533, XP093090564, DOI: 10.1038/s41467-018-05886-y
HUA HUI, KONG QINGBIN, ZHANG HONGYING, WANG JIAO, LUO TING, JIANG YANGFU: "Targeting mTOR for cancer therapy", JOURNAL OF HEMATOLOGY & ONCOLOGY, vol. 12, no. 71, 1 December 2019 (2019-12-01), pages 1 - 19, XP055839513, DOI: 10.1186/s13045-019-0754-1
PAREJA FRESIA, BRANDES ALISSA H., BASILI THAIS, SELENICA PIER, GEYER FELIPE C., FAN DAN, DA CRUZ PAULA ARNAUD, KUMAR RAHUL, BROWN : "Loss-of-function mutations in ATP6AP1 and ATP6AP2 in granular cell tumors", NATURE COMMUNICATIONS, vol. 9, no. 1, 30 August 2018 (2018-08-30), pages 3533, XP093090564, DOI: 10.1038/s41467-018-05886-y
HUA HUI, KONG QINGBIN, ZHANG HONGYING, WANG JIAO, LUO TING, JIANG YANGFU: "Targeting mTOR for cancer therapy", JOURNAL OF HEMATOLOGY & ONCOLOGY, vol. 12, no. 71, 1 December 2019 (2019-12-01), pages 1 - 19, XP055839513, DOI: 10.1186/s13045-019-0754-1
Attorney, Agent or Firm:
SCIHEAD IP LAW FIRM (CN)
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