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Overview

Small molecule degraders of small ubiquitin-related modifier 1 (SUMO1) induce SUMO1 degradation in colon cancer cells and inhibits the cancer cell growth; however, it is unclear how SUMO1 degradation leads to the anticancer activity of the degraders. Genome-wide CRISPR-Cas9 knockout screen has identified StAR-related lipid transfer domain containing 7 (StarD7) as a critical gene for the degrader's anticancer activity. Here, we show that both StarD7 mRNA and protein are overexpressed in human colon cancer and its knockout significantly reduces colon cancer cell growth and xenograft progression. The treatment with the SUMO1 degrader lead compound HB007 reduces StarD7 mRNA and protein levels and increases endoplasmic reticulum (ER) stress and reactive oxygen species (ROS) production in colon cancer cells and three-dimensional (3D) organoids. The study further provides a novel mechanism of the compound anticancer activity that SUMO1 degrader-induced decrease of StarD7 occur through degradation of SUMO1, deSUMOylation and degradation of T cell-specific transcription 4 (TCF4) and thereby inhibition of its transcription of StarD7 in colon cancer cells, 3D organoids and patient-derived xenografts (PDX).

13 Oct 2021·Science Translational MedicineQ1 · MEDICINE

Ubiquitination and degradation of SUMO1 by small-molecule degraders extends survival of mice with patient-derived tumors

Q1 · MEDICINE

Article

Author: Higgins, Ryan K. ; Mosley, Amber L. ; Hauck, Paula M. ; Lo, Ho-Yin ; Wijeratne, Aruna B. ; Hao, Chunhai ; Hamdouchi, Chafiq ; Jiang, Wen ; Blanck, Maximilian ; Jung, Sung Han ; Kim, Daeho ; Li, Jing ; le Sage, Carlos ; Bellail, Anita C. ; Jin, Hong Ri ; Zhao, Yin Quan ; Shekhar, Anantha ; Ghosh, Manali ; Cross, Benedict C.S.

Small-molecule degraders of SUMO1 induce its ubiquitination and degradation through binding of CAPRIN1 in tumor cells in vitro and in vivo.

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Pipeline

Pipeline Snapshot as of 01 Dec 2024

The statistics for drugs in the Pipeline is the current organization and its subsidiaries are counted as organizations,Early Phase 1 is incorporated into Phase 1, Phase 1/2 is incorporated into phase 2, and phase 2/3 is incorporated into phase 3

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