BI-2493
[CAS# 2937344-16-4]

Identification

• Classification: Biochemical >> Inhibitor >> G protein coupled receptor(GPCR & G Protein)
• Name: BI-2493
• Synonyms: KRAS INHIBITOR; (7S)-2'-amino-3-[2-[(2S)-2-methylpiperazin-1-yl]pyrimidin-4-yl]spiro[5,6-dihydro-4H-1,2-benzoxazole-7,4'-6,7-dihydro-5H-1-benzothiophene]-3'-carbonitrile; (S)-2-amino-3'-(2-((S)-2-methylpiperazin-1-yl)pyrimidin-4-yl)-5',6,6',7-tetrahydro-4'H,5H-spiro[benzo[b]thiophene-4,7'-benzo[d]isoxazole]-3-carbonitrile
• Molecular Formula: C₂₄H₂₇N₇OS
• Molecular Weight: 461.58
• CAS Registry Number: 2937344-16-4
• SMILES: C[C@H]1CNCCN1C2=NC=CC(=N2)C3=NOC4=C3CCC[C@@]45CCCC6=C5C(=C(S6)N)C#N

Properties

• Density: 1.4±0.1 g/cm³ Calc.^*
• Boiling point: 774.2±70.0 ºC 760 mmHg (Calc.)^*
• Flash point: 422.0±35.7 ºC (Calc.)^*
• Index of refraction: 1.697 (Calc.)^*

^* Calculated using Advanced Chemistry Development (ACD/Labs) Software.

Safety Data

• Hazard Symbols: GHS07 Warning
• Hazard Statements: H302-H315-H319
• Precautionary Statements: P501-P270-P264-P280-P302+P352-P337+P313-P305+P351+P338-P362+P364-P332+P313-P301+P312+P330

Discovory and Applicatios

BI-2493 is a synthetic small-molecule compound developed as a non-covalent inhibitor of KRAS, a member of the RAS family of GTPases that plays a central role in regulating cellular processes such as growth, survival, and differentiation. Mutations in KRAS are among the most prevalent oncogenic alterations found in human cancers, particularly in tumors of the pancreas, colon, and lung. These mutations often lead to constitutive activation of KRAS signaling, making the protein a key target in cancer therapy. The development of selective KRAS inhibitors has been a major goal in medicinal chemistry and oncology research.

BI-2493 was derived through a series of structural optimizations from earlier compounds aimed at selectively targeting KRAS mutations. It was designed to act on both wild-type and mutant KRAS isoforms by binding to the GDP-bound inactive conformation of the protein. This allosteric inhibition prevents KRAS from transitioning to its active, GTP-bound form, thereby interrupting downstream signaling pathways that promote cell proliferation and survival. Unlike mutation-specific inhibitors, BI-2493 demonstrates broader activity across several oncogenic KRAS variants, including G12D, G12V, and A146T.

The compound has been studied primarily in preclinical settings, where it demonstrated effective inhibition of KRAS-driven signaling in a variety of cellular models. Its mechanism of action involves the stabilization of the inactive state of KRAS, which prevents it from interacting with key effector proteins such as RAF kinases. This blockade leads to a suppression of the MAPK signaling cascade, a pathway frequently hyperactivated in KRAS-mutant cancers.

BI-2493 is also distinguished by its high selectivity for KRAS over other small GTPases, minimizing off-target interactions. This selectivity is critical for reducing the potential for unwanted side effects associated with inhibition of related proteins in non-cancerous cells. The compound’s pharmacokinetic properties have been tailored to achieve sufficient bioavailability and metabolic stability, enabling its use in in vivo experimental models of cancer.

In animal models, BI-2493 has been shown to reduce tumor growth in xenografts derived from KRAS-mutant cancer cell lines. These findings support the compound’s potential utility as a therapeutic agent, particularly for cancers that are otherwise difficult to treat due to the lack of effective KRAS-targeted drugs. The ability to inhibit both wild-type and mutant KRAS forms also opens the possibility of using BI-2493 in a broader spectrum of patients whose tumors express different KRAS isoforms.

Beyond its therapeutic implications, BI-2493 is valuable as a chemical probe for elucidating the biological functions of KRAS in normal and malignant cells. By modulating KRAS activity in a controlled manner, researchers can investigate the consequences of its inhibition on cell signaling networks, gene expression profiles, and resistance mechanisms. These studies are essential for identifying predictive biomarkers and for designing rational combination therapies that may enhance the efficacy of KRAS inhibition.

BI-2493 is part of an emerging class of KRAS inhibitors that address longstanding challenges in drugging this target. Its non-covalent, allosteric binding mechanism provides an alternative approach to covalent inhibitors that target only specific mutations. This broader mode of action, coupled with its selectivity and favorable pharmacological profile, underscores its promise as a candidate for further development in cancer therapy. Continued investigation into its biological effects and therapeutic potential is ongoing in laboratory and translational research settings.

References

2023. Pan-KRAS inhibitor disables oncogenic signalling and tumour growth. Nature, 618(7963).
DOI: 10.1038/s41586-023-06123-3