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Targeting of SOS1: from SOS1 Activators to Proteolysis Targeting Chimeras

The most frequent mutated oncogene KRAS in lung cancer is targeted by KRAS G12C-directed drugs, such as Sotorasib and Adagrasib. Still, other alleles frequently expressed in pancreatic and colon cancer may be attacked indirectly by hitting the guanine nucleotide exchange factor (GEF) SOS1 that loads and activates KRAS. The first modulators of SOS1 were found to act as agonists and defined as a hydrophobic pocket at the catalytic site. High throughput screenings resulted in the detection of SOS1 inhibitors Bay-293 and BI-3406 comprising amino quinazoline scaffolds optimized for binding to the pocket by various substituents. The first inhibitor, BI-1701963, is in clinical studies alone or in combination with a KRAS inhibitor, a MAPK inhibitor or chemotherapeutics. An optimized agonist, VUBI-1, shows activity against tumor cells by destructive overactivation of cellular signaling. This agonist was used to formulate proteolysis targeting chimera (PROTAC), that labels SOS1 for degradation by proteasomal degradation through a linked VHL E3 ligase ligand. This PROTAC exhibited the highest SOS1-directed activity due to target destruction, recycling and removal of SOS1 as a scaffolding protein. Although other first PROTACs have entered clinical trials, each conjugate must be meticulously adapted as an efficient clinical drug.

 

Comments:

It appears that you are providing information about the targeting of the KRAS oncogene and the development of drugs and compounds aimed at inhibiting its activity. Here's a summary of the key points you mentioned:

1. The KRAS oncogene is frequently mutated in lung, pancreatic, and colon cancers.

2. KRAS G12C-directed drugs, such as Sotorasib and Adagrasib, specifically target the G12C mutation of KRAS in lung cancer.

3. For other alleles of KRAS expressed in pancreatic and colon cancer, indirect targeting is achieved by inhibiting the guanine nucleotide exchange factor (GEF) SOS1. SOS1 loads and activates KRAS.

4. The first modulators of SOS1 were agonists that targeted a hydrophobic pocket at the catalytic site of SOS1.

5. High-throughput screenings led to the discovery of SOS1 inhibitors, including Bay-293 and BI-3406, which have amino quinazoline scaffolds optimized for binding to the pocket with various substituents.

6. BI-1701963 is an SOS1 inhibitor that is being studied in clinical trials alone or in combination with a KRAS inhibitor, a MAPK inhibitor, or chemotherapeutics.

7. VUBI-1 is an optimized agonist that overactivates cellular signaling, leading to destructive effects on tumor cells.

8. VUBI-1 was used to formulate a proteolysis targeting chimera (PROTAC), which labels SOS1 for degradation by the proteasomal degradation pathway via a linked VHL E3 ligase ligand.

9. This SOS1-directed PROTAC showed high activity by targeting SOS1 for destruction, recycling, and removal as a scaffolding protein.

10. While other PROTACs have entered clinical trials, each conjugate must be carefully adapted to become an efficient clinical drug.

It's important to note that my knowledge cutoff is in September 2021, so there might be more recent developments or advancements in this field that I'm not aware of.

Related Products

Cat.No. Product Name Information
S8826 BAY-293 BAY-293 selectively inhibits the KRAS-SOS1 interaction with an IC50 of 21 nM.

Related Targets

Ras