6E6E

DGY-06-116, a novel and selective covalent inhibitor of SRC kinase

Summary for 6E6E

• Entry DOI: 10.2210/pdb6e6e/pdb
• Descriptor: Proto-oncogene tyrosine-protein kinase Src, N-(2-chloro-6-methylphenyl)-2-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-4-{[2-(propanoylamino)phenyl]amino}pyrimidine-5-carboxamide (3 entities in total)
• Functional Keywords: proto-oncogene tyrosine-protein kinase src, transferase, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 8
• Total formula weight: 258043.85

Authors

Gurbani, D.,Bera, A.,Westover, K. (deposition date: 2018-07-24, release date: 2019-07-31, Last modification date: 2024-11-06)

Primary citation

Gurbani, D.,Du, G.,Henning, N.J.,Rao, S.,Bera, A.K.,Zhang, T.,Gray, N.S.,Westover, K.D.
Structure and Characterization of a Covalent Inhibitor of Src Kinase.
Front Mol Biosci, 7:81-81, 2020

PubMed Abstract: Unregulated Src activity promotes malignant processes in cancer, but no Src-directed targeted therapies are used clinically, possibly because early Src inhibitors produce off-target effects leading to toxicity. Improved selective Src inhibitors may enable Src-directed therapies. Previously, we reported an irreversible Src inhibitor, DGY-06-116, based on the hybridization of dasatinib and a promiscuous covalent kinase probe SM1-71. Here, we report biochemical and biophysical characterization of this compound. An x-ray co-crystal structure of DGY-06-116: Src shows a covalent interaction with the kinase p-loop and occupancy of the back hydrophobic kinase pocket, explaining its high potency, and selectivity. However, a reversible analog also shows similar potency. Kinetic analysis shows a slow inactivation rate compared to other clinically approved covalent kinase inhibitors, consistent with a need for p-loop movement prior to covalent bond formation. Overall, these results suggest that a strong reversible interaction is required to allow sufficient time for the covalent reaction to occur. Further optimization of the covalent linker may improve the kinetics of covalent bond formation.

PubMed: 32509799
DOI: 10.3389/fmolb.2020.00081

Experimental method

X-RAY DIFFRACTION (2.15 Å)