Small molecule recognition of c-Src via the Imatinib-binding conformation

Area of Science:

• Biochemistry
• Medicinal Chemistry
• Structural Biology

Background:

• Imatinib is a selective Abl kinase inhibitor, not inhibiting the related c-Src kinase.
• This selectivity has guided kinase drug discovery for 15 years.
• A hypothesis suggests Abl adopts an inactive DFG-out conformation, unlike c-Src, explaining Imatinib's binding.

Purpose of the Study:

• To challenge the hypothesis that c-Src cannot bind inhibitors in its DFG-out conformation.
• To discover novel inhibitors targeting the c-Src DFG-out state.
• To understand the structural basis for differential kinase selectivity.

Main Methods:

• Structure-activity relationship studies.
• X-ray crystallography.
• Biochemical assays to assess kinase inhibition.

Main Results:

• Discovery of novel small molecule inhibitors targeting c-Src.
• Confirmation that these inhibitors bind to the c-Src DFG-out conformation.
• Structural data revealing how inhibitors induce this conformation in c-Src.

Conclusions:

• Small molecules can induce the unfavorable DFG-out conformation in c-Src.
• This finding refutes the previous hypothesis regarding c-Src's inability to adopt this state.
• Provides new insights into designing selective kinase inhibitors, potentially impacting cancer drug discovery.