Description

Product Description

Lorlatinib (PF-06463922) is a highly potent, orally active, and selective small-molecule inhibitor targeting ALK and ROS1 kinases. Designed for oncology research, Lorlatinib exhibits strong activity against both wild-type and mutant forms of ALK, including clinically relevant resistance mutations such as ALKL1196M, ALKG1269A, ALK1151Tins, and ALKG1202R. Its ATP-competitive mechanism allows it to block kinase activity effectively, inhibiting downstream signaling pathways that promote tumor cell proliferation, survival, and metastasis.

The compound is characterized by high brain penetration, enabling research into central nervous system (CNS) metastases, particularly in ALK- and ROS1-driven non-small cell lung cancer (NSCLC). Lorlatinib has Kis of <0.025 nM, <0.07 nM, and 0.7 nM for ROS1, wild-type ALK, and ALKL1196M, respectively, demonstrating exceptional potency. Preclinical studies also show IC50s of 14–113 nM against various ALK mutants, confirming its strong inhibitory effects across multiple oncogenic variants.

Lorlatinib has been applied in diverse preclinical oncology research scenarios. Its selectivity profile reduces off-target interactions, making it a valuable tool to study ALK/ROS1 signaling, evaluate drug resistance mechanisms, and investigate combination therapeutic strategies. Researchers utilize Lorlatinib to model ALK- or ROS1-positive tumors, examine pharmacodynamics and pharmacokinetics, and understand molecular mechanisms driving tumor growth and metastasis.

The compound’s high potency, selectivity, and brain-penetrant properties have facilitated numerous in vitro and in vivo studies. For example, Lorlatinib can be used to study kinase inhibition in cancer cell lines expressing ALK or ROS1 fusion proteins, assess resistance mutations, and evaluate tumor progression in xenograft models. Its effectiveness in preclinical CNS metastasis models provides insights into therapeutic approaches for patients with brain tumors secondary to ALK/ROS1-driven cancers.

In addition to oncology research, Lorlatinib serves as a valuable tool to investigate kinase biology. It enables mechanistic studies of ALK/ROS1-dependent pathways, cellular proliferation, apoptosis, and signal transduction. Researchers can employ Lorlatinib to explore combination therapies with chemotherapeutic agents, immunotherapies, or targeted inhibitors, supporting translational research and potential drug development.

Overall, Lorlatinib is a versatile research compound, offering robust inhibition of ALK and ROS1 kinases, high selectivity, brain penetration, and broad applicability in preclinical cancer studies. Its properties make it ideal for investigating drug resistance, combination treatments, tumor biology, and CNS metastases, establishing it as a critical tool in oncology research pipelines.

Product Specifications

Mechanism of Action

Lorlatinib exerts its pharmacological activity primarily through ATP-competitive inhibition of ALK and ROS1 kinases. By occupying the ATP-binding site, Lorlatinib prevents phosphorylation of ALK/ROS1 substrates, thereby blocking downstream signaling pathways that mediate tumor cell proliferation, survival, angiogenesis, and metastasis.

Lorlatinib’s high selectivity for ALK and ROS1 minimizes off-target kinase interactions, providing researchers with a reliable tool to study oncogenic signaling. It is effective against both wild-type and mutant ALK variants, including:

• ALKL1196M: A gatekeeper mutation that confers resistance to first-generation ALK inhibitors.

• ALKG1269A: A mutation leading to reduced efficacy of crizotinib and ceritinib.

• ALK1151Tins: An insertion mutation associated with clinical resistance.

• ALKG1202R: A rare mutation observed in patients with relapsed ALK-positive NSCLC.

The compound’s brain-penetrant properties enable it to target tumors within the CNS, which is critical for studying brain metastases in ALK- or ROS1-positive cancers. Lorlatinib effectively reduces tumor burden in CNS xenograft models, demonstrating its preclinical relevance.

In addition to kinase inhibition, Lorlatinib can modulate downstream signaling pathways, including PI3K/AKT, RAS/MEK/ERK, and STAT3. By suppressing these pathways, Lorlatinib influences cell cycle progression, apoptosis, and angiogenesis, providing researchers with a comprehensive tool for mechanistic studies.

Lorlatinib has been used in combination with other targeted inhibitors to explore synergistic effects and overcome resistance mechanisms in preclinical models. Its ATP-competitive mechanism, combined with high selectivity and CNS penetration, makes it a versatile compound for exploring kinase biology, resistance pathways, and potential combination therapeutic strategies.

Side Effects

As a laboratory research compound, Lorlatinib should be handled with appropriate biosafety and chemical safety procedures. Preclinical studies suggest that exposure at high concentrations can lead to cytotoxic effects in vitro. It is essential to follow institutional protocols for safe handling, storage, and disposal.

Side effects observed in preclinical models may include cell growth inhibition or apoptosis in non-target cell populations at high doses. Lorlatinib is not intended for clinical use or human administration. Researchers should employ proper protective equipment and containment procedures during experiments.

Keywords

Lorlatinib, PF-06463922, ROS1 inhibitor, ALK inhibitor, ALK mutant, brain-penetrant kinase inhibitor, anticancer research, NSCLC research, preclinical oncology, kinase signaling, CNS metastases, drug resistance, ATP-competitive inhibitor,High quality peptides

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Disclaimer

All products listed are intended for laboratory research use only and not for human or veterinary use. They are not drugs, medical devices, or diagnostics and should not be administered to humans or animals. Researchers must handle all materials in accordance with institutional biosafety and chemical safety guidelines. The information provided is for scientific reference only and does not imply therapeutic efficacy, safety, or regulatory approval.