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Targeted Protein Degradation and Drug Discovery



WEBINAR

Targeted protein degradation using chimeric small molecules, such as PROTAC® degraders and specific and nongenetic inhibitors of apoptosis protein (IAP)-dependent protein erasers (SNIPERs), has attracted attention as a method for degrading intracellular target proteins via the ubiquitin-proteasome system (UPS). However, it is difficult to develop such degraders in the absence of suitable small-molecule ligands for the target proteins, such as for transcription factors (TFs). Therefore, we constructed the chimeric molecule LCL-ER(dec), which consists of a decoy oligonucleotide that can bind to estrogen receptor α (ERα) and an IAP ligand, LCL161 (LCL), in a click reaction. LCL-ER(dec) was found to selectively degrade ERα via the UPS. These findings will be applicable to the development of other oligonucleotide-type degraders that target different TFs.

Targeted protein degradation by chimeric small molecules is a novel strategy for drug discovery. Dr. Naito & his team have developed a series of specific and non-genetic IAP-dependent protein erasers (SNIPERs) and proteolysis targeting chimeras (PROTAC®) against various proteins including estrogen receptor alpha in breast cancers, androgen receptor in prostate cancers, BCR-ABL oncogenic kinase in chronic myelogenous leukemia cells, TACC3 protein overexpressed in various cancer cells, HPGDS and so on. These SNIPERs and PROTAC® degraders recruit E3 ubiquitin ligases to the target proteins in cells, thereby inducing ubiquitylation and proteasomal degradation of the target proteins. Generally, the degradation is rapid and highly specific to the targets, and the reduced protein level sustains even after drug removal. Substitution of the target ligands allows the development of novel degrader chimeras against the proteins of interest, therefore PROTAC® degraders and SNIPERs attract attention as a platform technology for novel drug discovery. In addition to the forced ubiquitylation by chimeric molecules, inhibition of de-ubiquitylase also induces targeted degradation of some proteins such as BCR-ABL. In the symposium, Dr. Naito will share an overview of the technologies to induce proteasomal degradation of target proteins, and their application for drug discovery and basic research.

This webinar will cover:

  1. Induction of proteasomal degradation of target proteins by chemical compounds including PROTAC® degraders, SNIPERs and E3 modulators.
  2. Advantage of protein degradation over functional inhibition as a drug.
  3. How to develop PROTAC® degraders and SNIPERs against proteins of your interest.
  4. Future prospect of the targeted protein degradation as a modarity for novel drug discovery.

Speakers

Mikihiko Naito, Ph.D.

Mikihiko Naito, Ph.D.

Graduate School of Pharmaceutical Sciences, The University of Tokyo

Project Professor

Project Professor (2020-present), The University of Tokyo, Tokyo, Japan
Chief (2009-2020), National Institute of Health Sciences, Tokyo, Japan
Associate Professor (1995-2009), The University of Tokyo, Tokyo, Japan
Assistant Professor (1989-1995), The University of Tokyo, Tokyo, Japan
Post-doctoral fellow (1987-1989), Cancer Institute, Japanese Foundation for Cancer Research, Tokyo, Japan.
Ph.D. (1987), Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo, Japan

Moderators

Ray Chen, Ph.D.

Ray Chen, Ph.D.

Merck

Senior Marketing Manager, Lab Specialty Chemicals Asia Pacific

Hiroshi Komatsu

Hiroshi Komatsu

Merck

Marketing Specialist, Asia Pacific Chemistry

PROTAC® is a registered trademark of Arvinas Operations, Inc., and is used under license.

Webinar Information

Chemistry and synthesis

  • Protein degredation
  • Duration:1hr 30min

  • Language:English

  • Session 1:Tue, June 21, 2022 1:00 PM SGT

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