Open Access iconOpen Access

REVIEW

Development of PROTACS degrading KRAS and SOS1

by GERHARD HAMILTON*, MARIE-THERESE EGGERSTORFER, SANDRA STICKLER

Institute of Pharmacology, Medical University of Vienna, Vienna, 1090, Austria

* Corresponding Author: GERHARD HAMILTON. Email: email

Oncology Research 2024, 32(8), 1257-1264. https://doi.org/10.32604/or.2024.051653

Abstract

The Kirsten rat sarcoma virus—son of sevenless 1 (KRAS-SOS1) axis drives tumor growth preferentially in pancreatic, colon, and lung cancer. Now, KRAS G12C mutated tumors can be successfully treated with inhibitors that covalently block the cysteine of the switch II binding pocket of KRAS. However, the range of other KRAS mutations is not amenable to treatment and the G12C-directed agents Sotorasib and Adragrasib show a response rate of only approximately 40%, lasting for a mean period of 8 months. One approach to increase the efficacy of inhibitors is their inclusion into proteolysis-targeting chimeras (PROTACs), which degrade the proteins of interest and exhibit much higher antitumor activity through multiple cycles of activity. Accordingly, PROTACs have been developed based on KRAS- or SOS1-directed inhibitors coupled to either von Hippel-Lindau (VHL) or Cereblon (CRBN) ligands that invoke the proteasomal degradation. Several of these PROTACs show increased activity in vitro and in vivo compared to their cognate inhibitors but their toxicity in normal tissues is not clear. The CRBN PROTACs containing thalidomide derivatives cannot be tested in experimental animals. Resistance to such PROTACS arises through downregulation or inactivation of CRBN or factors of the functional VHL E3 ubiquitin ligase. Although highly active KRAS and SOS1 PROTACs have been formulated their clinical application remains difficult.

Graphic Abstract

Development of PROTACS degrading KRAS and SOS1

Keywords


Cite This Article

APA Style
HAMILTON, G., EGGERSTORFER, M., STICKLER, S. (2024). Development of PROTACS degrading KRAS and SOS1. Oncology Research, 32(8), 1257-1264. https://doi.org/10.32604/or.2024.051653
Vancouver Style
HAMILTON G, EGGERSTORFER M, STICKLER S. Development of PROTACS degrading KRAS and SOS1. Oncol Res. 2024;32(8):1257-1264 https://doi.org/10.32604/or.2024.051653
IEEE Style
G. HAMILTON, M. EGGERSTORFER, and S. STICKLER, “Development of PROTACS degrading KRAS and SOS1,” Oncol. Res., vol. 32, no. 8, pp. 1257-1264, 2024. https://doi.org/10.32604/or.2024.051653



cc Copyright © 2024 The Author(s). Published by Tech Science Press.
This work is licensed under a Creative Commons Attribution 4.0 International License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
  • 1335

    View

  • 369

    Download

  • 0

    Like

Share Link