Structural Mechanism of the Pan-BCR-ABL Inhibitor Ponatinib (AP24534): Lessons for Overcoming Kinase Inhibitor Resistance

• Published in: Chemical biology & drug design 2011-01, Vol.77 (1), p.1-11
• Main Authors: Zhou, Tianjun, Commodore, Lois, Huang, Wei-Sheng, Wang, Yihan, Thomas, Mathew, Keats, Jeff, Xu, Qihong, Rivera, Victor M, Shakespeare, William C, Clackson, Tim, Dalgarno, David C, Zhu, Xiaotian
• Format: Article
• Language: English
• Subjects: 60 APPLIED LIFE SCIENCES; Animals; ANTINEOPLASTIC DRUGS; AP24534; BASIC BIOLOGICAL SCIENCES; Benzamides; Cell Line, Tumor; Crystallography, X-Ray; drug discovery; Drug Resistance, Neoplasm - drug effects; Drug Resistance, Neoplasm - genetics; ENZYME INHIBITORS; Fluoroimmunoassay; Fusion Proteins, bcr-abl - antagonists & inhibitors; Fusion Proteins, bcr-abl - genetics; Fusion Proteins, bcr-abl - metabolism; GENE MUTATIONS; Imatinib Mesylate; Imidazoles - chemical synthesis; Imidazoles - pharmacology; Imidazoles - therapeutic use; kinase; Leukemia, Myelogenous, Chronic, BCR-ABL Positive - drug therapy; Leukemia, Myelogenous, Chronic, BCR-ABL Positive - enzymology; Leukemia, Myelogenous, Chronic, BCR-ABL Positive - genetics; Mice; MUTANTS; Mutation - drug effects; MUTATIONS; MYELOID LEUKEMIA; PHOSPHOTRANSFERASES; Piperazines - chemistry; Piperazines - pharmacology; Piperazines - therapeutic use; ponatinib; Protein Binding - drug effects; Protein Kinase Inhibitors - chemistry; Protein Kinase Inhibitors - pharmacology; Protein Kinase Inhibitors - therapeutic use; Pyridazines - chemical synthesis; Pyridazines - pharmacology; Pyridazines - therapeutic use; Pyrimidines - chemistry; Pyrimidines - pharmacology; Pyrimidines - therapeutic use; RESIDUES; Structure-Activity Relationship; STRUCTURE-ACTIVITY RELATIONSHIPS; structure-based drug design; TYROSINE; X-ray crystallography
• ISSN: 1747-0277; 1747-0285
• DOI: 10.1111/j.1747-0285.2010.01054.x

The BCR-ABL inhibitor imatinib has revolutionized the treatment of chronic myeloid leukemia. However, drug resistance caused by kinase domain mutations has necessitated the development of new mutation-resistant inhibitors, most recently against the T315I gatekeeper residue mutation. Ponatinib (AP24534) inhibits both native and mutant BCR-ABL, including T315I, acting as a pan-BCR-ABL inhibitor. Here, we undertook a combined crystallographic and structure-activity relationship analysis on ponatinib to understand this unique profile. While the ethynyl linker is a key inhibitor functionality that interacts with the gatekeeper, virtually all other components of ponatinib play an essential role in its T315I inhibitory activity. The extensive network of optimized molecular contacts found in the DFG-out binding mode leads to high potency and renders binding less susceptible to disruption by single point mutations. The inhibitory mechanism exemplified by ponatinib may have broad relevance to designing inhibitors against other kinases with mutated gatekeeper residues.