Lorlatinib | CAS No. 1454846-35-5

Description

Product Description

Lorlatinib (PF-06463922) is a third-generation tyrosine kinase inhibitor (TKI) designed to target anaplastic lymphoma kinase (ALK) and ROS1 fusions, two oncogenic drivers found in a subset of non-small cell lung cancer (NSCLC) and other malignancies. Its development was aimed at overcoming resistance mutations that compromise earlier-generation ALK inhibitors such as crizotinib, ceritinib, and alectinib.

Research Background

ALK and ROS1 rearrangements drive tumorigenesis by constitutive activation of downstream signaling pathways, including MAPK, PI3K-AKT, and JAK-STAT. These pathways promote proliferation, survival, and metastasis of tumor cells. Lorlatinib’s rational design emphasizes high potency, broad spectrum of mutant inhibition, and CNS penetration, enabling it to treat brain metastases, a common site of progression in ALK-positive NSCLC.

Key Features

• Potent Activity:

  • ROS1 inhibition: Ki < 0.025 nM

  • Wild-type ALK inhibition: Ki < 0.07 nM

  • ALK L1196M resistance mutant: Ki = 0.7 nM

• CNS Penetration: Optimized structure allows effective blood-brain barrier crossing, making it highly effective in treating brain metastases.

• Broad Resistance Coverage: Effective against multiple ALK mutations, including L1196M, G1269A, 1151Tins, and G1202R.

• ATP-Competitive: Lorlatinib binds to the ATP-binding pocket of ALK/ROS1, preventing phosphorylation and downstream signaling.

Research Applications

• Oncology Research: A core molecule for investigating ALK/ROS1-driven tumor biology.

• Drug Resistance Studies: Serves as a model compound for studying resistance mechanisms in kinase-targeted therapy.

• Preclinical Models: Effective in xenograft and cell line studies for NSCLC and other malignancies.

• Biochemical Characterization: Valuable for kinase profiling and structural biology research.

Lorlatinib is thus a next-generation tool for researchers studying targeted cancer therapies, drug resistance, and CNS drug delivery.

Product Specifications

Mechanism of Action

Lorlatinib exerts its effect by binding to the ATP-binding site of ALK and ROS1 kinases, preventing phosphorylation and subsequent activation of downstream oncogenic signaling pathways.

1. Targeted Kinase Inhibition

• ALK: In ALK-positive NSCLC, Lorlatinib blocks ALK autophosphorylation, thereby halting proliferative signals.

• ROS1: In ROS1-rearranged cancers, inhibition prevents aberrant signaling through MAPK and PI3K-AKT pathways.

2. Resistance Mutation Coverage

Earlier ALK inhibitors often fail due to mutations in the ALK kinase domain. Lorlatinib is structurally designed to fit within mutated kinase pockets, retaining potency.

• Effective against ALK L1196M (“gatekeeper” mutation).

• Active against ALK G1202R, one of the most challenging mutations for first- and second-generation inhibitors.

• Inhibits other resistance variants, including 1151Tins and G1269A.

3. CNS Penetration

Lorlatinib is designed with low P-glycoprotein efflux liability and high lipophilicity, enabling it to cross the blood-brain barrier efficiently. This makes it particularly valuable for treating intracranial metastases, a frequent progression site in NSCLC.

4. Downstream Pathways

By blocking ALK/ROS1 activity, Lorlatinib suppresses:

• MAPK/ERK signaling → reducing proliferation.

• PI3K/AKT signaling → inducing apoptosis.

• JAK/STAT3 signaling → inhibiting tumor survival and immune evasion.

Thus, Lorlatinib effectively halts tumor progression by targeting both primary oncogenic drivers and resistance mechanisms.

Side Effects

As a research compound, safety data is limited, but experimental and clinical reports suggest potential effects:

• Metabolic Changes: Can cause hyperlipidemia and hypercholesterolemia in vivo.

• CNS-Related: Due to high brain penetration, may influence cognitive, mood, and speech functions in experimental models.

• Cardiovascular: Potential to prolong QT interval in cell or animal studies.

• Hepatotoxicity: Altered liver enzymes observed in certain models.

• Drug Resistance: Long-term use in models may induce secondary resistance mutations.

Laboratory Precautions

• Handle with protective clothing, gloves, and eyewear.

• Use in BSL-2 facilities.

• Avoid inhalation or direct contact.

Disclaimer

For research use only. Not intended for human or veterinary use, diagnosis, or treatment.

Keywords

Lorlatinib, PF-06463922, ALK inhibitor, ROS1 inhibitor, brain-penetrant TKI, kinase inhibitor research, NSCLC targeted therapy, anticancer research, CAS 1454846-35-5. Peptide Manufacturer-Wholesaler

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