2. Academic Validation
  3. Discovery of electrophilic degraders that exploit SNAr chemistry

Discovery of electrophilic degraders that exploit SNAr chemistry

  • bioRxiv. 2024 Sep 27:2024.09.25.615094. doi: 10.1101/2024.09.25.615094.
Zhe Zhuang 1 2,  Woong Sub Byun 1 2,  Zuzanna Kozicka 3 4,  Brendan G Dwyer 1,  Katherine A Donovan 5 6,  Zixuan Jiang 7,  Hannah M Jones 1,  Dinah M Abeja 5 6,  Meredith N Nix 7,  Jianing Zhong 7,  Mikołaj Słabicki 3 4,  Eric S Fischer 5 6,  Benjamin L Ebert 3 4 8,  Nathanael S Gray 1
Affiliations

Affiliations

  • 1 Department of Chemical and Systems Biology, ChEM-H, and Stanford Cancer Institute, Stanford School of Medicine, Stanford University, Stanford, CA, USA.
  • 2 These authors contributed equally: Zhe Zhuang, Woong Sub Byun.
  • 3 Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
  • 4 Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • 5 Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA.
  • 6 Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA, USA.
  • 7 Department of Chemistry, Stanford University, Stanford, CA, USA.
  • 8 Howard Hughes Medical Institute, Boston, MA, USA.
PMID: 39386645 DOI: 10.1101/2024.09.25.615094
Abstract

Targeted covalent inhibition (TCI) and targeted protein degradation (TPD) have proven effective in pharmacologically addressing formerly 'undruggable' targets. Integration of both methodologies has resulted in the development of electrophilic degraders where recruitment of a suitable E3 ubiquitin Ligase is achieved through formation of a covalent bond with a cysteine nucleophile. Expanding the scope of electrophilic degraders requires the development of electrophiles with tempered reactivity that enable selective Ligase recruitment and reduce cross-reactivity with Other cellular nucleophiles. In this study, we report the use of chemical moieties that enable nucleophilic aromatic substitution (SNAr) reactions in the rational design of electrophilic protein degraders. Appending an SNAr covalent warhead to several preexisting small molecule inhibitors transformed them into degraders, obviating the need for a defined E3 Ligase recruiter. The SNAr covalent warhead is versatile; it can recruit various E3 Ligases, including DDB1 and CUL4 associated factor 11 (DCAF11), DDB1 and CUL4 associated factor 16 (DCAF16), and possibly Others. The incorporation of an SNAr covalent warhead into the BRD4 Inhibitor led to the discovery of degraders with low picomolar degradation potency. Furthermore, we demonstrate the broad applicability of this approach through rational functional switching from kinase inhibitors into potent degraders.

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