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Structural basis and selectivity of sulfatinib binding to FGFR and CSF-1R
Qianmeng Lin1,2, Shuyan Dai1,2, Lingzhi Qu1,2
1Department of Oncology, NHC Key Laboratory of Cancer Proteomics, State Local Joint Engineering Laboratory for Anticancer Drugs, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, China.
Abstract:
Acquired drug resistance poses a challenge for single-target FGFR inhibitors, leading to the development of dual- or multi-target FGFR inhibitors. Sulfatinib is a multi-target kinase inhibitor for treating neuroendocrine tumors, selectively targeting FGFR1/CSF-1R. To elucidate the molecular mechanisms behind its binding and kinase selectivity, we determined the crystal structures of sulfatinib with FGFR1/CSF-1R. The results reveal common structural features and distinct conformational adaptability of sulfatinib in response to FGFR1/CSF-1R binding. Further biochemical and structural analyses disclose sensitivity of sulfatinib to FGFR/CSF-1R gatekeeper mutations. The insensitivity of sulfatinib to FGFR gatekeeper mutations highlights the indispensable interactions with the hydrophobic pocket for FGFR selectivity, whereas the rotatory flexibility may enable sulfatinib to overcome CSF-1RT663I. This study not only sheds light on the structural basis governing sulfatinib's FGFR/CSF-1R inhibition, but also provides valuable insights into the rational design of dual- or multi-target FGFR inhibitors with selectivity for CSF-1R and sensitivity to gatekeeper mutations.
Insights
Sulfatinib, a multi-target inhibitor, effectively targets FGFR1 and CSF-1R. Its structural mechanisms reveal insights into overcoming drug resistance and designing novel kinase inhibitors.
Area of Science:
- Molecular biology
- Structural biology
- Pharmacology
Background:
- Acquired drug resistance limits single-target kinase inhibitors.
- Multi-target inhibitors like sulfatinib offer a strategy to overcome resistance.
- Sulfatinib targets FGFR1 and CSF-1R, relevant in neuroendocrine tumors.
Purpose of the Study:
- To elucidate the molecular mechanisms of sulfatinib binding to FGFR1 and CSF-1R.
- To understand the structural basis of sulfatinib's kinase selectivity.
- To investigate sulfatinib's sensitivity to gatekeeper mutations in FGFR and CSF-1R.
Main Methods:
- X-ray crystallography to determine structures of sulfatinib with FGFR1 and CSF-1R.
- Biochemical assays to assess kinase inhibition and sensitivity to mutations.
- Structural analysis to identify key binding interactions and conformational adaptability.
Main Results:
- Crystal structures revealed common binding features and distinct conformational adaptability of sulfatinib for FGFR1 and CSF-1R.
- Sulfatinib demonstrated sensitivity to specific FGFR and CSF-1R gatekeeper mutations.
- Insensitivity to FGFR gatekeeper mutations was linked to hydrophobic pocket interactions, while rotatory flexibility aided CSF-1R inhibition.
Conclusions:
- The study provides a structural understanding of sulfatinib's inhibition of FGFR1 and CSF-1R.
- Findings highlight the importance of hydrophobic interactions for FGFR selectivity.
- Insights guide the rational design of multi-target FGFR inhibitors with improved selectivity and resistance profiles.
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