Structural insights into the potency and selectivity of covalent pan-FGFR inhibitors

FIIN-2, TAS-120 (Futibatinib) and PRN1371 are highly potent pan-FGFR covalent inhibitors targeting the p-loop cysteine of FGFR proteins, of which TAS-120 and PRN1371 are currently in clinical trials. It is critical to analyze their target selectivity and their abilities to overcome gatekeeper mutations. In this study, we demonstrate that FIIN-2 and TAS-120 form covalent adducts with SRC, while PRN1371 does not. FIIN-2 and TAS-120 inhibit SRC and YES activities, while PRN1371 does not. Moreover, FIIN-2, TAS-120 and PRN1371 exhibit different potencies against different FGFR gatekeeper mutants. In addition, the co-crystal structures of SRC/FIIN-2, SRC/TAS-120 and FGFR4/PRN1371 complexes reveal structural basis for kinase targeting and gatekeeper mutations. Taken together, our study not only provides insight into the potency and selectivity of covalent pan-FGFR inhibitors, but also sheds light on the development of next-generation FGFR covalent inhibitors with high potency, high selectivity, and stronger ability to overcome gatekeeper mutations.

 

Comments:

The information you provided describes a study that focuses on the analysis of three highly potent pan-FGFR (fibroblast growth factor receptor) covalent inhibitors: FIIN-2, TAS-120 (also known as Futibatinib), and PRN1371. These inhibitors target the p-loop cysteine of FGFR proteins. It is important to assess their target selectivity and their ability to overcome gatekeeper mutations, which are mutations that occur at a specific residue in the kinase domain and can confer resistance to inhibitors.

The study reveals several key findings:

FIIN-2 and TAS-120 form covalent adducts with SRC, a non-FGFR kinase. PRN1371, on the other hand, does not form such adducts. This suggests that FIIN-2 and TAS-120 may have off-target effects on SRC, while PRN1371 does not.

FIIN-2 and TAS-120 inhibit the activities of SRC and YES, which are kinases, while PRN1371 does not have an inhibitory effect on these kinases. This indicates that FIIN-2 and TAS-120 have broader kinase inhibitory profiles compared to PRN1371.

The three inhibitors (FIIN-2, TAS-120, and PRN1371) exhibit different potencies against various FGFR gatekeeper mutants. Gatekeeper mutations can render inhibitors less effective, so it is crucial to assess their ability to overcome these mutations. The study highlights the varying potencies of the inhibitors against different FGFR gatekeeper mutants, suggesting differences in their effectiveness.

Co-crystal structures of the SRC/FIIN-2, SRC/TAS-120, and FGFR4/PRN1371 complexes were determined. These structures provide insights into how the inhibitors target the kinases and interact with the gatekeeper mutations.

Understanding the structural basis of inhibitor binding and its impact on gatekeeper mutations can aid in the development of next-generation FGFR covalent inhibitors with improved potency, selectivity, and the ability to overcome resistance.

In summary, this study contributes to our understanding of the potency, selectivity, and ability to overcome gatekeeper mutations of covalent pan-FGFR inhibitors. The findings can guide the development of more effective inhibitors for targeting FGFR proteins, which are involved in various cellular processes and have implications in cancer and other diseases.