Development of PROTACS degrading KRAS and SOS1

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.

Keywords: Cereblon; Kirsten rat sarcoma virus (KRAS); Proteolysis-targeting chimeras (PROTACs); Son of sevenless 1 (SOS1); Von Hippel-Lindau.

Figure 1. Function of a KRAS (Kirsten Rat Sarcoma virus) degrader. Activation of RTKs is transferred to KRAS via GRB2, SHC2, and SOS1, and its loading with GTP is followed by downstream activation of signaling cascades. In targeted protein degradation a protein degrader binds to KRAS and recruits an E3 ubiquitin ligase that directs the POI to the proteasome. Abbreviations are as follows: Receptor Tyrosine Kinase (RTK), factor receptor-bound protein 2 (GRB2), SHC Adaptor Protein 2 (SHC2), phosphate (P), Son of Sevenless (SOS1), Kirsten Rat Sarcoma virus (KRAS), Guanidine diphosphate (GDP), Guanidine triphosphate (GTP), GTPase activating proteins (GAP), E3 ligase (E3).