From: RAS signaling and immune cells: a sinister crosstalk in the tumor microenvironment
Classification | Strategies | Mechanism | Examples | References |
---|---|---|---|---|
Indirectly blocking of RAS signals | Inhibition of RAS membrane localization | Inhibition of farnesylation or PDEδ | Lonafarnib Tipifarnib Salirasib | |
Inhibition of RAS signaling pathway transduction | SHP2 inhibitors | SHP099 TNO155 RMC-4630 | ||
SOS1 inhibitors | BAY-293 BI-3406 | |||
RAF-MEK-ERK inhibitors | LXH-254 Selumetinib (AZD6244) Tizaterkib (AZD0364) | |||
PI3K-AKT-mTOR inhibitors | Alpelisib (BYL719) Lpatasertib Everolimus | |||
Direct targeting of RAS proteins | Small molecular inhibitors (covalent interactions) | cysteine pocket for KRAS G12C | Sotorasib Adagrasib | |
arginase pocket for KRAS G12R | α,β-Diketoamide ligand | [97] | ||
serine pocket for KRAS G12S | β-Lactone ligand | [98] | ||
Small molecular inhibitors (non-covalent interactions) | Triple complex with KRAS G12D and CypA | RMC9805 | [99] | |
Salt bridge for KRAS G12D | MRTX-1133 TH-Z835 | |||
RAS gene silencing and editing | RNAi CRISPR | siRNAs, shRNAs, CRISPR/Cas9 (DNA), CRISPR/Cas13 (RNA) | ||
RAS degraders | PROTAC, linker-based degraders, direct proteolysis degraders | LC-2 KP-14 |