Brigatinib
[CAS# 1197953-54-0]

Identification

• Classification: API >> Inhibitor drug
• Name: Brigatinib
• Synonyms: 5-Chloro-N4-[2-(dimethylphosphinyl)phenyl]-N2-[2-methoxy-4-[4-(4-methyl-1-piperazinyl)-1-piperidinyl]phenyl]-2,4-pyrimidinediamine; AP 26113
• Molecular Formula: C₂₉H₃₉ClN₇O₂P
• Molecular Weight: 584.09
• CAS Registry Number: 1197953-54-0
• EC Number: 849-234-2
• SMILES: CN1CCN(CC1)C2CCN(CC2)C3=CC(=C(C=C3)NC4=NC=C(C(=N4)NC5=CC=CC=C5P(=O)(C)C)Cl)OC

Properties

• Solubility: Practically insoluble (0.028 g/L) (25 °C), Calc.^*
• Density: 1.31±0.1 g/cm³ (20 °C 760 Torr), Calc.^*

^* Calculated using Advanced Chemistry Development (ACD/Labs) Software V11.02 (©1994-2016 ACD/Labs)

Safety Data

• Hazard Symbols: GHS6;GHS08;GHS09 Danger
• Risk Statements: H301-H361-H372-H410
• Safety Statements: P203-P260-P264-P270-P273-P280-P301+P316-P318-P319-P321-P330-P391-P405-P501

Hazard Classification

Hazard	Class	Category Code	Hazard Statement
Reproductive toxicity	Repr.	2	H361
Chronic hazardous to the aquatic environment	Aquatic Chronic	1	H410
Specific target organ toxicity - repeated exposure	STOT RE	1	H372
Acute toxicity	Acute Tox.	3	H301

Discovery and Applications

Brigatinib is a targeted cancer therapy developed by ARIAD Pharmaceuticals, now part of Takeda Pharmaceuticals. It was discovered through extensive research aimed at finding effective treatments for non-small cell lung cancer (NSCLC) with specific genetic mutations. In the early 2010s, researchers focused on designing inhibitors for anaplastic lymphoma kinase (ALK), a protein that, when mutated, can drive cancer progression. Brigatinib, identified through these efforts, exhibited strong inhibition of ALK and other relevant mutations. Its development involved a series of preclinical and clinical trials, demonstrating its efficacy in overcoming resistance to first-generation ALK inhibitors. In 2017, brigatinib received FDA approval for the treatment of ALK-positive metastatic NSCLC, providing a new hope for patients with this challenging condition.

Brigatinib is used as a first-line treatment for ALK-positive metastatic NSCLC. It offers a significant improvement in progression-free survival compared to traditional chemotherapy, making it a preferred option for newly diagnosed patients.

One of brigatinib's key applications is its ability to overcome resistance to first-generation ALK inhibitors like crizotinib. Many patients with ALK-positive NSCLC develop resistance to initial therapies, and brigatinib provides an effective alternative, prolonging patient survival and improving quality of life.

Brigatinib has demonstrated efficacy in treating brain metastases associated with ALK-positive NSCLC. Its ability to penetrate the blood-brain barrier and target cancer cells in the central nervous system makes it a crucial therapy for patients with metastatic brain lesions, which are common in advanced lung cancer.

Ongoing research is exploring the potential of brigatinib in combination with other targeted therapies and immunotherapies. Combining brigatinib with immune checkpoint inhibitors or other kinase inhibitors could enhance its efficacy and provide new treatment avenues for patients with complex genetic profiles or those who have developed resistance to current treatments.

While its primary application is in NSCLC, researchers are investigating brigatinib's effectiveness in other cancers with relevant genetic mutations. This research could potentially expand the drug's applicability beyond lung cancer, offering new hope for patients with different types of cancer.

Brigatinib not only extends survival but also helps manage symptoms better compared to chemotherapy, leading to improved quality of life for patients. Its targeted nature means fewer side effects and better tolerance, which is crucial for patients undergoing long-term cancer treatment.

References

2024. Therapeutic effects of an ALK inhibitor, brigatinib, on lung large cell neuroendocrine carcinoma with EML4-ALK fusion. Respiratory Investigation.
DOI: 10.1016/j.resinv.2024.09.013

2024. Systematic review and network meta-analysis of lorlatinib with comparison to other anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitors (TKIs) as first-line treatment for ALK-positive advanced non-small cell lung cancer (NSCLC). Lung Cancer (Amsterdam, Netherlands).
DOI: 10.1016/j.lungcan.2024.107968

2024. Comparative Efficacy and Safety of Lorlatinib Versus Alectinib and Lorlatinib Versus Brigatinib for ALK-Positive Advanced/Metastatic NSCLC: Matching-Adjusted Indirect Comparisons. Clinical Lung Cancer.
DOI: 10.1016/j.cllc.2024.08.003