The preclinical profile of crizotinib for the treatment of non-small-cell lung cancer and other neoplastic disorders

Abstract

Introduction: The critical role of the activity of the nucleophosmin- anaplastic lymphoma kinase (NPM-ALK) fusion protein in anaplastic large-cell lymphoma prompted drug discovery programs directed against ALK. Drug discovery efforts increased after finding that about 4% of non-small-cell lung cancers (NSCLCs) possess an EML4-ALK fusion protein.

Areas covered: The author provides a review of the development of crizotinib, an orally effective c-Met and ALK protein kinase inhibitor. The article highlights its beginning with the X-ray crystallographic structure of a lead compound (PHA-0665752) bound to the active site of the kinase domain of c-Met.

Expert opinion: Studies of patients with EML4-ALK–positive NSCLC showed that crizotinib was clinically effective and led to its approval in August 2011. The use of lipophilic efficiency played a crucial role in the development of crizotinib from a lead c-Met inhibitor. The use of X-ray crystal structures from lead compounds, bound to their targets, is increasing in the drug discovery process owing to its effectiveness. That the drug also inhibits ALK and ALK-fusion proteins was serendipitous, however. The discovery of the EML4-ALK fusion protein in some NSCLC patients has led to the testing and rapid approval of the compound.

Keywords::

• anaplastic lymphoma kinase
• c-Met
• epidermal growth factor receptor
• Hsp90
• lung cancer
• protein kinase
• structure-based drug design
• targeted cancer therapy

Acknowledgment

The author thanks JJ Cui for insightful discussion and LM Roskoski for bibliographic assistance.

Notes

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