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Small molecule inhibitor of ubiquitin-binding enzyme E2T

A technology of ubiquitin-conjugating enzymes and ubiquitination, which is applied in the field of small molecule inhibitors of ubiquitin-conjugating enzyme E2T, and can solve the unreported problems such as the association between UBE2T and RACK1

Active Publication Date: 2022-02-18
LANZHOU UNIV SECOND HOSPITAL
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

No association between UBE2T and RACK1 has been reported so far

Method used

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  • Small molecule inhibitor of ubiquitin-binding enzyme E2T
  • Small molecule inhibitor of ubiquitin-binding enzyme E2T
  • Small molecule inhibitor of ubiquitin-binding enzyme E2T

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0063] Example 1: M435-1279 binds and inhibits the activity of UBE2T

[0064] Flag-UBE2T and HA-RACK1 were transfected into HEK-293T cells, and 5'GFP (Flag-tagged GFP) was used as a control to verify the interaction between UBE2T and RACK1 by co-immunoprecipitation experiments ( figure 1 a), and Western blotting was performed by transfecting a fixed amount of RACK1 and different amounts of UBE2T. It was found that the more UBE2T was transferred, the lower the protein level of RACK1 was, proving that UBE2T can degrade RACK1 ( figure 1 b). Transfection of Flag-RACK1, untagged UBE2T, and HA-tagged different mutated ubiquitin chains into HEK-293T cells revealed that the K48R mutated ubiquitin chains could not be ubiquitinated, so the effect of UBE2T on RACK1 was dependent on (mediated degradation) of the K48 chain ( figure 1 c).

[0065] By microthermophoresis experiments ( figure 2 ) to test the binding ability of UBE2T and M435-1279, the KD value is 50.5 micromolar.

[006...

Embodiment 2

[0067] Example 2: M435-1279 in the treatment of gastric cancer

[0068] Clonogenic experiments ( Figure 4 a) Proved that the ability of colony formation was significantly weakened after adding M435-1279 to HGC27 and AGS in gastric cancer cells. Transweel experiment ( Figure 4 b) It proves that after adding M435-1279 to HGC27 and AGS in cancer cells, the invasion ability is significantly weakened. Gastric cancer cell MKN45 was used to plant subcutaneously in nude mice until the tumor grew to 80mm 3 When using M435-1279 for intratumoral injection (5mg / kg / day), and using DMSO as a control, it was found that the tumor growth rate in mice injected with M435-1279 was significantly slowed down ( Figure 4 c-e).

[0069] In conclusion, M435-1279 can significantly inhibit the progression of gastric cancer.

[0070]

[0071]

[0072]

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Abstract

The present invention relates to a small molecule inhibitor of ubiquitin-binding enzyme E2T (UBE2T) and use thereof in the treatment of cancer.

Description

technical field [0001] The present invention relates to small molecule inhibitors of ubiquitin-conjugating enzyme E2T (UBE2T) and their application in the treatment of cancer. [0002] Background of the invention [0003] Ubiquitin-conjugating enzyme E2T (UBE2T) is a member of the ubiquitin-conjugating enzyme E2 family. It was first discovered in the study of Fanconi anemia and is involved in DNA damage repair as an important member of the Fanconi signaling pathway. The crystal structure of UBE2T is known. It is located on chromosome chrl q32.1. Its open reading frame (ORF) consists of 6 exons and 5 introns. The span on the chromosome is 10.3kb, and it has a characteristic The conserved domain has a conserved 86th cysteine ​​residue as its active site, which can form a thioester bond with ubiquitin molecules, and its C-terminus has an extended sequence, which is related to the localization of UBE2T to the nucleus. Studies have reported that UBE2T plays an important role in t...

Claims

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Application Information

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IPC IPC(8): A61K31/4365A61P7/06A61P35/00
CPCA61K31/4365A61P7/06A61P35/00
Inventor 焦作义俞泽元蒋祥彦孙辉
Owner LANZHOU UNIV SECOND HOSPITAL
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