Structural Mechanisms Determining Inhibition of the Collagen Receptor DDR1 by Selective and Multi-Targeted Type II Kinase Inhibitors

2014/04/23 by Peter Canning, Li Tan, Kiki Chu +3 · 100 citations
Biochemistry, Genetics and Molecular Biology · Chemistry · Medicine · #Biochemistry #Biology #Chemistry #Chronic Myeloid Leukemia Treatments #Collagen receptor #DDR1 #HER2/EGFR in Cancer Research #Integrin #Kinase #Melanoma and MAPK Pathways #Pharmacology #Receptor #Receptor tyrosine kinase

paper · pdf · doi:10.1016/j.jmb.2014.04.014

published in Journal of Molecular Biology 426(13), 2457-2470 (Elsevier BV)

openalex publication_date 2014/04/23 · openalex created_date 2025/10/10 · openalex updated_date 2026/08/06

Abstract

The discoidin domain receptors (DDRs), DDR1 and DDR2, form a unique subfamily of receptor tyrosine kinases that are activated by the binding of triple-helical collagen. Excessive signaling by DDR1 and DDR2 has been linked to the progression of various human diseases, including fibrosis, atherosclerosis and cancer. We report the inhibition of these unusual receptor tyrosine kinases by the multi-targeted cancer drugs imatinib and ponatinib, as well as the selective type II inhibitor DDR1-IN-1. Ponatinib is identified as the more potent molecule, which inhibits DDR1 and DDR2 with an IC50 of 9nM. Co-crystal structures of human DDR1 reveal a DFG-out conformation (DFG, Asp-Phe-Gly) of the kinase domain that is stabilized by an unusual salt bridge between the activation loop and αD helix. Differences to Abelson kinase (ABL) are observed in the DDR1 P-loop, where a β-hairpin replaces the cage-like structure of ABL. P-loop residues in DDR1 that confer drug resistance in ABL are therefore accommodated outside the ATP pocket. Whereas imatinib and ponatinib bind potently to both the DDR and ABL kinases, the hydrophobic interactions of the ABL P-loop appear poorly satisfied by DDR1-IN-1 suggesting a structural basis for its DDR1 selectivity. Such inhibitors may have applications in clinical indications of DDR1 and DDR2 overexpression or mutation, including lung cancer.

Cited by

• Discoidin domain receptor 1 (DDR1) kinase as target for structure-based drug discovery. [europepmc]
• Characterization of DDR2 Inhibitors for the Treatment of DDR2 Mutated Nonsmall Cell Lung Cancer. [europepmc]
• Discoidin Domain Receptors: Potential Actors and Targets in Cancer. [europepmc]
• Structure-Based Design of Tetrahydroisoquinoline-7-carboxamides as Selective Discoidin Domain Receptor 1 (DDR1) Inhibitors. [europepmc]
• Multi-organ Site Metastatic Reactivation Mediated by Non-canonical Discoidin Domain Receptor 1 Signaling. [europepmc]
• Discoidin domain receptor 1 kinase activity is required for regulating collagen IV synthesis. [europepmc]
• Collagen induces activation of DDR1 through lateral dimer association and phosphorylation between dimers. [europepmc]
• Multitasking discoidin domain receptors are involved in several and specific hallmarks of cancer. [europepmc]
• Signaling by discoidin domain receptor 1 in cancer metastasis. [europepmc]
• Recent Studies on Ponatinib in Cancers Other Than Chronic Myeloid Leukemia. [europepmc]
• What Makes a Kinase Promiscuous for Inhibitors? [europepmc]
• 3D culture enhances chemoresistance of ALL Jurkat cell line by increasing DDR1 expression. [europepmc]
• BCR-ABL Tyrosine Kinase Inhibitors: Which Mechanism(s) May Explain the Risk of Thrombosis? [europepmc]
• Discovery of VU6015929: A Selective Discoidin Domain Receptor 1/2 (DDR1/2) Inhibitor to Explore the Role of DDR1 in Antifibrotic Therapy. [europepmc]
• Collagen Kinase Receptors as Potential Therapeutic Targets in Metastatic Colon Cancer. [europepmc]
• Discoidin Domain Receptor-1 (DDR1) is Involved in Angiolymphatic Invasion in Oral Cancer. [europepmc]
• Discoidin Domain Receptor 1 is a therapeutic target for neurodegenerative diseases. [europepmc]
• DrugSpaceX: a large screenable and synthetically tractable database extending drug space. [europepmc]
• Silencing of sinusoidal DDR1 reduces murine liver metastasis by colon carcinoma. [europepmc]
• Design and Synthesis of DDR1 Inhibitors with a Desired Pharmacophore Using Deep Generative Models. [europepmc]
• Discoidin domain receptors orchestrate cancer progression: A focus on cancer therapies. [europepmc]
• Extracellular matrix and its therapeutic potential for cancer treatment. [europepmc]
• The Journey of DDR1 and DDR2 Kinase Inhibitors as Rising Stars in the Fight Against Cancer. [europepmc]
• Evolution of Functional Diversity in the Holozoan Tyrosine Kinome. [europepmc]
• Collagen Remodeling along Cancer Progression Providing a Novel Opportunity for Cancer Diagnosis and Treatment. [europepmc]

Related

• Targeted DDR1Treatment Strategy Enhances PD-1Immunotherapy Efficacy against Gastric Cancer
• Synthesis andPreclinical Evaluation of DDR1-TargetedRadiotracers for Colorectal Cancer Diagnosis
• Autophosphorylation of oncoprotein TEL-ABL in myeloid and lymphoid cells confers resistance to the allosteric ABL inhibitor asciminib
• Structural basis for the potent and selective binding of LDN-212854 to the BMP receptor kinase ALK2
• Cdc2-like kinases: structure, biological function and therapeutic targets for diseases