Structural study of ponatinib in inhibiting SRC kinase

Area of Science:

• Biochemistry
• Molecular Biology
• Structural Biology

Background:

• Ponatinib is a multi-target tyrosine kinase inhibitor designed to overcome imatinib resistance in BCR-ABL mutations, including the ABL^T315I gatekeeper mutation.
• While ponatinib's mechanisms against BCR-ABL are known, its interaction with SRC, particularly gatekeeper mutations, is less understood.

Purpose of the Study:

• To investigate ponatinib's inhibitory effects on wild-type SRC and SRC gatekeeper mutants.
• To elucidate the structural basis for ponatinib's differential activity against SRC and other kinases with gatekeeper mutations.

Main Methods:

• Biochemical and cellular assays were used to assess ponatinib's inhibition of wild-type and mutant SRC kinase.
• Crystal structure determination of ponatinib complexed with the SRC kinase domain.

Main Results:

• Ponatinib effectively inhibited wild-type SRC kinase activity.
• Ponatinib failed to inhibit SRC gatekeeper mutants in both biochemical and cellular assays.
• Structural analysis provided insights into the differential effects of ponatinib on SRC compared to other kinases with gatekeeper mutations.

Conclusions:

• SRC gatekeeper mutations confer resistance to ponatinib.
• The structural findings offer a potential explanation for ponatinib's varying efficacy across different kinases with gatekeeper mutations.
• Understanding SRC resistance mechanisms can inform the future design of inhibitors targeting SRC family kinases.