1-(6,7-Dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N3-[(7S)-6,7,8,9-tetrahydro-7-(1-pyrrolidinyl)-5H-benzocyclohepten-2-yl]-1H-1,2,4-triazole-3,5-diamine
[CAS# 1037624-75-1]

Identification

• Classification: Biochemical >> Inhibitor >> Protein tyrosine kinase
• Name: 1-(6,7-Dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N3-[(7S)-6,7,8,9-tetrahydro-7-(1-pyrrolidinyl)-5H-benzocyclohepten-2-yl]-1H-1,2,4-triazole-3,5-diamine
• Synonyms: R 428
• Molecular Formula: C₃₀H₃₄N₈
• Molecular Weight: 506.64
• CAS Registry Number: 1037624-75-1
• EC Number: 894-430-3
• SMILES: C1CCN(C1)[C@H]2CCC3=C(CC2)C=C(C=C3)NC4=NN(C(=N4)N)C5=NN=C6C(=C5)CCCC7=CC=CC=C76

Properties

• Density: 1.4±0.1 g/cm³ Calc.^*
• Boiling point: 799.6±70.0 °C 760 mmHg (Calc.)^*
• Flash point: 437.4±35.7 °C (Calc.)^*
• Solubility: DMSO:$lessThan$10mg/mL (Expl.)
• Index of refraction: 1.768 (Calc.)^*

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

Safety Data

• Hazard Symbols: GHS07 Warning
• Risk Statements: H302
• Safety Statements: P264-P270-P301+P317-P330-P501

Hazard Classification

Hazard	Class	Category Code	Hazard Statement
Acute toxicity	Acute Tox.	4	H302

Discovery and Applications

1-(6,7-Dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N₃-[(7S)-6,7,8,9-tetrahydro-7-(1-pyrrolidinyl)-5H-benzocyclohepten-2-yl]-1H-1,2,4-triazole-3,5-diamine, commonly known as bemcentinib, is a synthetic small-molecule inhibitor targeting the Axl receptor tyrosine kinase. This compound has been developed for its potential therapeutic applications in oncology and other diseases characterized by aberrant Axl signaling.

Bemcentinib's chemical structure comprises a triazole core linked to a pyridazinyl moiety and a substituted benzocycloheptenyl group, contributing to its high specificity and potency as an Axl inhibitor. The molecular formula is C₃₀H₃₄N₈, and it has a molecular weight of 506.64 g/mol. Its design allows for effective oral bioavailability and favorable pharmacokinetic properties, making it suitable for clinical development.

The discovery of bemcentinib was driven by the need to develop selective inhibitors of the Axl receptor, which plays a critical role in various cellular processes, including survival, proliferation, migration, and immune regulation. Overexpression and activation of Axl have been implicated in the progression and metastasis of several cancers, as well as in resistance to conventional therapies. By inhibiting Axl, bemcentinib aims to disrupt these pathological signaling pathways, thereby exerting antitumor effects.

Preclinical studies have demonstrated bemcentinib's efficacy in inhibiting Axl-mediated signaling, leading to reduced tumor cell proliferation, migration, and invasion. Additionally, it has been shown to enhance the sensitivity of cancer cells to chemotherapeutic agents and to modulate the tumor microenvironment, potentially improving immune responses against tumors.

In clinical settings, bemcentinib is being investigated for its therapeutic potential in various malignancies, including non-small cell lung cancer (NSCLC), acute myeloid leukemia (AML), and triple-negative breast cancer (TNBC). Clinical trials are assessing its safety, tolerability, and efficacy both as a monotherapy and in combination with other treatments, such as immune checkpoint inhibitors. These studies aim to establish bemcentinib's role in overcoming resistance to existing therapies and improving patient outcomes.

Beyond oncology, bemcentinib's immunomodulatory properties have prompted research into its application in other diseases characterized by dysregulated Axl signaling. Its ability to modulate immune responses and inhibit pathological cell signaling pathways suggests potential utility in treating fibrotic diseases and certain viral infections, although these applications are still under investigation.

From a chemical standpoint, bemcentinib is a yellow powder that is soluble in dimethyl sulfoxide (DMSO) and stable under standard storage conditions. Its synthesis involves the strategic assembly of its core triazole and pyridazinyl structures, followed by the introduction of the benzocycloheptenyl substituent. This synthetic route allows for the production of bemcentinib with high purity and consistency, essential for its use in clinical research.

In summary, bemcentinib represents a promising therapeutic agent targeting the Axl receptor tyrosine kinase. Its development underscores the importance of selective kinase inhibitors in modern pharmacotherapy, offering potential benefits in treating cancers and other diseases driven by aberrant Axl signaling. Ongoing clinical trials will further elucidate its efficacy and safety profile, potentially leading to new treatment options for patients with limited therapeutic alternatives.

References

2010. The Axl receptor tyrosine kinase is an adverse prognostic factor and a therapeutic target in esophageal adenocarcinoma. Cancer Biology & Therapy, 10(10).
DOI: 10.4161/cbt.10.10.13248

2023. TTD: Therapeutic Target Database describing target druggability information. Nucleic Acids Research, 52(D1).
DOI: 10.1093/nar/gkad751

2024. Brigatinib, a newly discovered AXL inhibitor, suppresses AXL-mediated acquired resistance to osimertinib in EGFR-mutated non-small cell lung cancer. Acta Pharmacologica Sinica, 45(6).
DOI: 10.1038/s41401-024-01237-4