Entrectinib
[CAS# 1108743-60-7]

Identification

• Classification: API >> Antineoplastic agents
• Name: Entrectinib
• Synonyms: N-[5-[(3,5-Difluorophenyl)methyl]-1H-indazol-3-yl]-4-(4-methyl-1-piperazinyl)-2-[(tetrahydro-2H-pyran-4-yl)amino]benzamide; RXDX 101
• Molecular Formula: C₃₁H₃₄F₂N₆O₂
• Molecular Weight: 560.64
• CAS Registry Number: 1108743-60-7
• EC Number: 816-298-8
• SMILES: CN1CCN(CC1)C2=CC(=C(C=C2)C(=O)NC3=NNC4=C3C=C(C=C4)CC5=CC(=CC(=C5)F)F)NC6CCOCC6

Properties

• Solubility: Insoluble (6.2E^-4 g/L) (25 °C), Calc.^*
• Density: 1.340±0.06 g/cm³ (20 °C 760 Torr), Calc.^*

^* Calculated using Advanced Chemistry Development (ACD/Labs) Software V11.02 (©1994-2017 ACD/Labs)

Safety Data

• Hazard Symbols: GHS07 Warning
• Risk Statements: H302-H315-H319-H335
• Safety Statements: P261-P305+P351+P338

Discovery and Applications

Entrectinib, a breakthrough in targeted cancer therapy, was discovered by scientists at Ignyta, a biotechnology company, in the early 2010s. This discovery emerged from efforts to develop selective inhibitors targeting specific genetic mutations associated with cancer growth. Entrectinib was designed to inhibit the activity of tropomyosin receptor kinases (TRKs) and the proto-oncogene tyrosine-protein kinase ROS1, which are involved in various cancers. The innovative approach aimed to create a drug that could target cancers driven by these genetic alterations, regardless of their tissue origin. The drug received accelerated approval from the FDA in August 2019, highlighting its significance in treating genetically defined cancers.

Entrectinib, marketed under the brand name Rozlytrek, has revolutionized the treatment of certain cancers through its mechanism as a tyrosine kinase inhibitor. By targeting specific genetic mutations, entrectinib offers a personalized approach to cancer therapy, showcasing the potential of precision medicine.

Entrectinib is primarily used to treat solid tumors that harbor NTRK gene fusions. These fusions lead to the production of TRK fusion proteins, which drive cancer cell proliferation. Entrectinib binds to and inhibits these proteins, resulting in tumor regression. This targeted approach allows for effective treatment across a variety of cancer types, including lung, colon, breast, and sarcoma, provided they exhibit NTRK fusions. The broad applicability of entrectinib for these fusion-positive tumors underscores its versatility and effectiveness.

Another significant application of entrectinib is in the treatment of ROS1-positive NSCLC. ROS1 rearrangements occur in a subset of NSCLC patients, leading to oncogenic activity. Entrectinib's ability to inhibit ROS1 kinase provides a powerful therapeutic option for these patients, offering improved outcomes and progression-free survival. This has been particularly beneficial for patients with advanced or metastatic disease, where traditional chemotherapy may be less effective.

One of entrectinib's notable features is its ability to penetrate the blood-brain barrier, making it effective against primary and metastatic brain tumors. Many patients with TRK or ROS1 fusion-positive cancers develop brain metastases, and entrectinib's CNS activity addresses this critical challenge. This property not only extends the drug's applicability but also significantly improves quality of life and survival rates for patients with CNS involvement.

Research continues to explore the full potential of entrectinib, including its efficacy in combination with other therapies and its role in different genetic contexts. Studies are investigating biomarkers that could predict patient response, aiming to refine and expand the use of entrectinib in precision oncology. Furthermore, the development of resistance to entrectinib is a focus of ongoing research, with efforts directed towards understanding and overcoming these mechanisms to sustain long-term efficacy.

References

2024. Entrectinib versus crizotinib in Asian patients with ROS1-positive non-small cell lung cancer: A matching-adjusted indirect comparison. Lung cancer (Amsterdam, Netherlands).
DOI: 10.1016/j.lungcan.2024.108018

2024. Cognitive and ataxic adverse events following entrectinib treatment in NTRK1 fusion gene-positive intrahepatic cholangiocarcinoma: a case report. Clinical Journal of Gastroenterology.
DOI: 10.1007/s12328-024-02076-w

2015. Durable Clinical Response to Entrectinib in NTRK1-Rearranged Non-Small Cell Lung Cancer. Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer.
DOI: 10.1097/01.jto.0000473485.38553.f0