Article ｜ 09 Feb 2024

WIKIMOLE of the week—Bl-2493 & Bl-2865

By TargetMol

 

BI-2493, catalog number: T72061, is a highly selective pan-KRAS inhibitor and a structural analogue of BI-2865. It exhibits similar anti-tumor activity to BI-2865, inhibiting tumor cell growth, and is used in research related to cancer diseases.

 

About KRAS

In common human cancer-causing genes, mutant RAS affects approximately 19% of tumors, making it one of the most prevalent oncogenic mutated genes in human cancers.

Among them, HRAS was first identified in 1982 as an oncogene resulting from a point mutation. Subsequently, NRAS and KRAS were also rapidly discovered. Since then, significant efforts have been made in the study of RAS. Among the three mutations in NRAS, HRAS, and KRAS, KRAS mutations are more common, frequently occurring in pancreatic ductal adenocarcinoma (PDAC), colorectal adenocarcinoma, and lung adenocarcinoma (LUAD), among others.

Mutant RAS proteins exhibit significant oncogenic effects, and tumor cells carrying mutant RAS demonstrate a more invasive phenotype. Patients with tumors harboring RAS mutations generally have a worse prognosis and shorter overall survival compared to those without RAS mutations. Therefore, the development of anti-tumor drugs targeting mutant RAS is imperative.

 

 

About KRAS inhibitors

(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.

 

Reference

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