What question did this study set out to answer?

To elucidate the structural and molecular mechanisms governing the inhibition and target selectivity of type II kinase inhibitors against the collagen receptors DDR1 and DDR2.

April 23, 2014Journal of Molecular BiologyOpen Access

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

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To elucidate the structural and molecular mechanisms governing the inhibition and target selectivity of type II kinase inhibitors against the collagen receptors DDR1 and DDR2.
Assessed biochemical inhibition of human DDR1 and DDR2 by the multi-targeted cancer drugs imatinib and ponatinib, alongside the selective inhibitor DDR1-IN-1.
Solved co-crystal structures of the human DDR1 kinase domain complexed with inhibitors to compare conformational features directly against Abelson kinase (ABL).
Ponatinib potently inhibited both DDR1 and DDR2 with an IC50 of 9 nM.
Co-crystal structures revealed a DFG-out kinase conformation stabilized by a unique salt bridge formed between the activation loop and the αD helix.
Structural divergence in the DDR1 P-loop, which adopts a β-hairpin rather than the cage-like fold of ABL, positions drug-resistance residues outside the ATP pocket and drives the selectivity of DDR1-IN-1.

Authors

PCPeter CanningLifeArc LTLi TanCentral South University KCKiki ChuUniversity of Wisconsin–Madison

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Implication

Structural analysis reveals how type II kinase inhibitors target DDR1 and DDR2, highlighting mechanisms of drug potency and selectivity in cancer therapy.

Cite This Study

Canning et al. (2014) studied this question.

synapsesocial.com/papers/69dbd9455b363cdf1c83608f https://doi.org/10.1016/j.jmb.2014.04.014

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Implication

Structural analysis reveals how type II kinase inhibitors target DDR1 and DDR2, highlighting mechanisms of drug potency and selectivity in cancer therapy.

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

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Discussion

Implication

Cite This Study

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

Key Points

Discussion

Implication

Cite This Study

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