2. Academic Validation
  3. Ubiquitination and degradation of SUMO1 by small-molecule degraders extends survival of mice with patient-derived tumors

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

  • Sci Transl Med. 2021 Oct 13;13(615):eabh1486. doi: 10.1126/scitranslmed.abh1486.
Anita C Bellail 1 2 3,  Hong Ri Jin 1,  Ho-Yin Lo 4,  Sung Han Jung 1,  Chafiq Hamdouchi 1,  Daeho Kim 1,  Ryan K Higgins 1,  Maximilian Blanck 5,  Carlos le Sage 5,  Benedict C S Cross 5,  Jing Li 6,  Amber L Mosley 2 7,  Aruna B Wijeratne 7,  Wen Jiang 8,  Manali Ghosh 8,  Yin Quan Zhao 1,  Paula M Hauck 1,  Anantha Shekhar 9,  Chunhai Hao 1 2 10
Affiliations

Affiliations

  • 1 Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
  • 2 Indiana University Melvin and Bren Simon Comprehensive Cancer Center, Indianapolis, IN 46202, USA.
  • 3 HB Therapeutics Inc., Indianapolis, IN 46202, USA.
  • 4 Synovel Laboratory LLC, Danbury, CT 06811, USA.
  • 5 Horizon Discovery, Cambridge, CB25 9TL, UK.
  • 6 Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, MI 48201, USA.
  • 7 Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
  • 8 Department of Biological Sciences, Markey Center for Structural Biology, Purdue University, West Lafayette, IN 47907, USA.
  • 9 Department of Psychiatry and Indiana Clinical and Translational Sciences Institute, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
  • 10 Department of Neurological Surgery, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
PMID: 34644148 DOI: 10.1126/scitranslmed.abh1486
Abstract

Discovery of small-molecule degraders that activate ubiquitin ligase–mediated ubiquitination and degradation of targeted oncoproteins in Cancer cells has been an elusive therapeutic strategy. Here, we report a Cancer cell–based drug screen of the NCI drug-like compounds library that enabled identification of small-molecule degraders of the small ubiquitin-related modifier 1 (SUMO1). Structure-activity relationship studies of analogs of the hit compound CPD1 led to identification of a lead compound HB007 with improved properties and Anticancer potency in vitro and in vivo. A genome-scale CRISPR-Cas9 knockout screen identified the substrate receptor F-box protein 42 (FBXO42) of cullin 1 (CUL1) E3 ubiquitin Ligase as required for HB007 activity. Using HB007 pull-down proteomics assays, we pinpointed HB007’s binding protein as the cytoplasmic activation/proliferation-associated protein 1 (CAPRIN1). Biolayer interferometry and compound competitive immunoblot assays confirmed the selectivity of HB007’s binding to CAPRIN1. When bound to CAPRIN1, HB007 induced the interaction of CAPRIN1 with FBXO42. FBXO42 then recruited SUMO1 to the CAPRIN1-CUL1-FBXO42 ubiquitin Ligase complex, where SUMO1 was ubiquitinated in several of human Cancer cells. HB007 selectively degraded SUMO1 in patient tumor–derived xenografts implanted into mice. Systemic administration of HB007 inhibited the progression of patient-derived brain, breast, colon, and lung cancers in mice and increased survival of the Animals. This Cancer cell–based screening approach enabled discovery of a small-molecule degrader of SUMO1 and may be useful for identifying other small-molecule degraders of oncoproteins.

Figures
Products
嗨！很高兴为您提供帮助！

尊敬的 MCE 客户您好，
请您选择所在区域，我们将转接对应客服为您服务！

热门区域

A

B

C

F

G

H

J

L

N

Q

S

T

X

Y

Z

热 A B C F G H J L N Q S T X Y Z