c-Src binds to the cancer drug Ruxolitinib with an active conformation

Area of Science:

• Biochemistry
• Structural Biology
• Pharmacology

Background:

• Ruxolitinib is an approved janus kinase (JAK) inhibitor for myeloproliferative neoplasms.
• Ruxolitinib exhibits weak inhibitory activity against Src kinase.
• No prior structural data existed for Ruxolitinib binding to any kinase.

Purpose of the Study:

• To determine the crystal structure of the c-Src kinase domain in complex with Ruxolitinib.
• To elucidate the binding mode of Ruxolitinib to c-Src.
• To compare Ruxolitinib's binding to c-Src and JAK1.

Main Methods:

• X-ray crystallography was used to determine the structure of c-Src kinase domain bound to Ruxolitinib at 2.26 Å resolution.
• Molecular docking was employed to analyze Ruxolitinib's interaction with a JAK1 structure.
• Comparative analysis of binding interactions and shape complementarity was performed.

Main Results:

• The crystal structure revealed Ruxolitinib binds to c-Src kinase in an active DFG-in conformation, classifying it as a type I inhibitor.
• Ruxolitinib forms key hydrogen bonds with Met341 and Thr338, along with van der Waals contacts within the c-Src binding pocket.
• Docking studies indicated Ruxolitinib also acts as a type I inhibitor for JAK1, with enhanced interactions and shape complementarity compared to c-Src.

Conclusions:

• Ruxolitinib functions as a type I inhibitor for both c-Src and JAK1 kinases.
• The structural and docking data highlight opportunities for modifying Ruxolitinib to enhance potency against c-Src.
• The findings provide a basis for developing novel, more effective c-Src inhibitors based on the Ruxolitinib scaffold.