Ras inhibitor
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Advances in RAS Inhibitors: Targeting Oncogenic Drivers in Cancer
Introduction to RAS Inhibitors
RAS proteins, particularly KRAS, are frequently mutated in human cancers, making them critical targets for cancer therapy. Despite their significance, RAS proteins have long been considered "undruggable" due to the lack of deep pockets for small molecule binding. However, recent breakthroughs have led to the development of several promising RAS inhibitors, offering new hope for targeting these oncogenic drivers.
Covalent Inhibitors Targeting KRAS(G12C)
A significant milestone in RAS inhibition was the discovery of covalent inhibitors targeting the KRAS(G12C) mutation. These inhibitors, such as AMG510 and MRTX849, bind to the mutant cysteine residue in KRAS(G12C) and lock the protein in its inactive GDP-bound state, preventing downstream signaling 12. These compounds have shown promising results in clinical trials, particularly for lung cancer patients harboring the KRAS(G12C) mutation . However, KRAS(G12C) mutations account for less than 15% of all RAS mutations, highlighting the need for broader-spectrum RAS inhibitors .
Structure-Based Drug Design (SBDD) and RAS-Effector Inhibitors
Structure-based drug design has been instrumental in developing new RAS inhibitors. By identifying novel surface pockets on both active and inactive forms of RAS, researchers have created small molecules that inhibit RAS-effector interactions. For instance, compounds like PPIN-1 and PPIN-2 have been developed by combining moieties from different RAS-binding molecules, resulting in improved efficacy in inhibiting RAS-effector interactions 34. This approach has expanded the catalog of RAS protein-protein interaction inhibitors, offering new avenues for therapeutic development.
Farnesyl-Protein Transferase Inhibitors
Another strategy to inhibit RAS involves targeting the post-translational modifications essential for its activation. Farnesylation, a critical modification for RAS activation, can be blocked by farnesyl-protein transferase (FPTase) inhibitors. Compounds such as (alpha-hydroxyfarnesyl)phosphonic acid have shown efficacy in inhibiting RAS processing in vivo, thereby preventing its activation and subsequent tumorigenesis 56.
SOS1 Inhibitors and GEF Targeting
Targeting guanine nucleotide exchange factors (GEFs) like SOS1, which facilitate the activation of RAS, represents another promising approach. SOS1 inhibitors disrupt the interaction between KRAS and SOS1, effectively reducing active RAS levels in tumor cells. For example, the compound BAY-293 selectively inhibits the KRAS-SOS1 interaction, demonstrating significant antiproliferative activity in cancer cells 78.
Peptide-Based Inhibitors
Peptide-based inhibitors have also emerged as a viable strategy for targeting specific RAS mutations. Using phage display technology, researchers have developed selective inhibitory peptides for KRAS(G12D), a common mutation in various cancers. These peptides, such as KRpep-2d, show high selectivity and potency in inhibiting KRAS(G12D) activity and downstream signaling, offering a new tool for targeted cancer therapy .
Conclusion
The development of RAS inhibitors has made significant strides, transforming the once "undruggable" RAS proteins into viable therapeutic targets. From covalent inhibitors targeting specific mutations to structure-based designs and peptide inhibitors, these advancements offer new hope for effectively treating RAS-driven cancers. Continued research and clinical trials will be crucial in expanding the applicability of these inhibitors to a broader range of RAS mutations and cancer types.
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