BI-2865

BI-2865 is a non-covalent pan-KRAS inhibitor.BI-2865 binds to KRAS WT, G12C, G12D, G12V, and G13D mutants with KD values of 6.9, 4.5, 32, 26, and 4.3 nM, respectively.BI-2865 showed antiproliferative activity in BaF3 cells expressing KRAS G12C, G12D, or G12V mutants. BI-2865 showed antiproliferative activity on BaF3 cells expressing KRAS G12C, G12D or G12V mutants with an average IC50 value of approximately 140 nM.

(1) KRAS-Specific Inhibitors. KRAS inhibitors can bind to the KRAS protein, rendering it in an inactive state. As mentioned earlier, KRASG12C mutant inhibitors (sotorasib & Adagrasib) irreversibly bind to KRAS, marking a pivotal milestone in clinical drug discovery. However, for another common mutation, KRASG12D (found in 33% of KRAS mutant tumors), there are currently no clinical drugs. Several inhibitors targeting KRASG12D are still in the development stage, with MRTX1133 (Catalog No. T9303) being a prominent candidate. Preclinical research results demonstrate the specific inhibitory activity of MRTX1133 in various tumor cell lines carrying the KRASG12D mutation. The drug has received FDA approval for a new drug clinical trial application and entered Phase I/II clinical trials in 2023. Although there is considerable research on KRAS mutations, an effective and widely applicable clinical drug has yet to be found. Hence, new methods are needed to identify a class of novel selective KRAS inhibitors. (2) Pan-KRAS Inhibitors. More than 100 mutation sites have been identified in RAS subtypes, with prominent mutation hotspots at G12, G13, and Q61. However, KRAS-specific inhibitor targets only G12C or G12D mutants, limiting clinical applications. To address these limitations, research teams have begun developing small molecule pan-KRAS inhibitors. Pan-KRAS inhibitors deactivate common KRAS cancer proteins without the need for covalent anchoring to specific mutant amino acids. These inhibitors can prevent reactivation through nucleotide exchange by preferentially targeting the non-active state of KRAS. Representative examples include BI-2865 and its analogue BI-2493.

2937327-93-8

BI-2865 is a non-covalent inhibitor with pan-KRAS potential. This inhibitor induces the inactivation of common KRAS oncoproteins (BI-2865 targets KRAS WT, G12C, G12D, G12V, and G13D mutants) without the need for covalent anchoring to specific mutant amino acids.

465.57

GPCR/G Protein|MAPK

0.9939

Pan-KRAS Inhibitors

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Ras