PF-06463922 is a potent and selective next-generation ROS1/ALK inhibitor capable of blocking crizotinib-resistant...

Area of Science:

• Oncology
• Molecular Biology
• Drug Discovery

Background:

• Oncogenic ROS1 fusion kinases are key drivers in various human cancers.
• Crizotinib is an effective treatment for ROS1 fusion-positive non-small cell lung cancer but resistance can emerge.
• Secondary mutations in ROS1 kinase are a significant mechanism of acquired resistance.

Purpose of the Study:

• To characterize the activity of PF-06463922, a novel ALK/ROS1 inhibitor, against ROS1 fusions and resistance mutations.
• To evaluate the in vitro and in vivo efficacy of PF-06463922.
• To assess PF-06463922's potential for treating central nervous system (CNS) metastases.

Main Methods:

• In vitro biochemical and cellular assays to assess kinase inhibition and cellular potency.
• Crystallography to determine the binding mode of PF-06463922 to ROS1 kinase.
• In vivo studies using tumor models harboring ROS1 fusions and mutations, including a glioblastoma model.

Main Results:

• PF-06463922 demonstrated subnanomolar cellular potency against oncogenic ROS1 fusions.
• It effectively inhibited crizotinib-refractory mutations ROS1(G2032R) and ROS1(G2026M).
• PF-06463922 exhibited superior inhibitory activity compared to crizotinib, ceritinib, and alectinib, with significant in vivo antitumor activity in various models, including CNS-penetrant glioblastoma.

Conclusions:

• PF-06463922 is a potent, orally available, CNS-penetrant inhibitor of ALK/ROS1.
• It shows promise for treating ROS1 fusion-positive cancers, including those with acquired resistance mutations.
• PF-06463922 represents a potential therapeutic strategy for overcoming crizotinib resistance and treating CNS disease.