Abstract
The human FGF receptors (FGFRs) play critical roles in various human cancers, and several FGFR inhibitors are currently under clinical investigation. Resistance usually results from selection for mutant kinases that are impervious to the action of the drug or from up-regulation of compensatory signaling pathways. Preclinical studies have demonstrated that resistance to FGFR inhibitors can be acquired through mutations in the FGFR gatekeeper residue, as clinically observed for FGFR4 in embryonal rhabdomyosarcoma and neuroendocrine breast carcinomas. Here we report on the use of a structure-based drug design to develop two selective, next-generation covalent FGFR inhibitors, the FGFR irreversible inhibitors 2 (FIIN-2) and 3 (FIIN-3). To our knowledge, FIIN-2 and FIIN-3 are the first inhibitors that can potently inhibit the proliferation of cells dependent upon the gatekeeper mutants of FGFR1 or FGFR2, which confer resistance to first-generation clinical FGFR inhibitors such as NVP-BGJ398 and AZD4547. Because of the conformational flexibility of the reactive acrylamide substituent, FIIN-3 has the unprecedented ability to inhibit both the EGF receptor (EGFR) and FGFR covalently by targeting two distinct cysteine residues. We report the cocrystal structure of FGFR4 with FIIN-2, which unexpectedly exhibits a "DFG-out" covalent binding mode. The structural basis for dual FGFR and EGFR targeting by FIIN3 also is illustrated by crystal structures of FIIN-3 bound with FGFR4 V550L and EGFR L858R. These results have important implications for the design of covalent FGFR inhibitors that can overcome clinical resistance and provide the first example, to our knowledge, of a kinase inhibitor that covalently targets cysteines located in different positions within the ATP-binding pocket.
| Original language | English |
|---|---|
| Pages (from-to) | E4869-E4877 |
| Journal | Proceedings of the National Academy of Sciences of the United States of America |
| Volume | 111 |
| Issue number | 45 |
| DOIs | |
| Publication status | Published - 2014 Nov 11 |
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Keywords
- Cancer drug resistance
- Drug discovery
- Kinase inhibitor
- Structure-based drug design
ASJC Scopus subject areas
- General
Cite this
Development of covalent inhibitors that can overcome resistance to first-generation FGFR kinase inhibitors. / Tan, Li; Wang, Jun; Tanizaki, Junko; Huang, Zhifeng; Aref, Amir R.; Rusan, Maria; Zhu, Su Jie; Zhang, Yiyun; Ercan, Dalia; Liao, Rachel G.; Capelletti, Marzia; Zhou, Wenjun; Hur, Wooyoung; Kim, Namdoo; Sim, Taebo; Gaudet, Suzanne; Barbie, David A.; Yeh, Jing Ruey Joanna; Yun, Cai Hong; Hammerman, Peter S.; Mohammadi, Moosa; Jänne, Pasi A.; Gray, Nathanael S.
In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 111, No. 45, 11.11.2014, p. E4869-E4877.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Development of covalent inhibitors that can overcome resistance to first-generation FGFR kinase inhibitors
AU - Tan, Li
AU - Wang, Jun
AU - Tanizaki, Junko
AU - Huang, Zhifeng
AU - Aref, Amir R.
AU - Rusan, Maria
AU - Zhu, Su Jie
AU - Zhang, Yiyun
AU - Ercan, Dalia
AU - Liao, Rachel G.
AU - Capelletti, Marzia
AU - Zhou, Wenjun
AU - Hur, Wooyoung
AU - Kim, Namdoo
AU - Sim, Taebo
AU - Gaudet, Suzanne
AU - Barbie, David A.
AU - Yeh, Jing Ruey Joanna
AU - Yun, Cai Hong
AU - Hammerman, Peter S.
AU - Mohammadi, Moosa
AU - Jänne, Pasi A.
AU - Gray, Nathanael S.
PY - 2014/11/11
Y1 - 2014/11/11
N2 - The human FGF receptors (FGFRs) play critical roles in various human cancers, and several FGFR inhibitors are currently under clinical investigation. Resistance usually results from selection for mutant kinases that are impervious to the action of the drug or from up-regulation of compensatory signaling pathways. Preclinical studies have demonstrated that resistance to FGFR inhibitors can be acquired through mutations in the FGFR gatekeeper residue, as clinically observed for FGFR4 in embryonal rhabdomyosarcoma and neuroendocrine breast carcinomas. Here we report on the use of a structure-based drug design to develop two selective, next-generation covalent FGFR inhibitors, the FGFR irreversible inhibitors 2 (FIIN-2) and 3 (FIIN-3). To our knowledge, FIIN-2 and FIIN-3 are the first inhibitors that can potently inhibit the proliferation of cells dependent upon the gatekeeper mutants of FGFR1 or FGFR2, which confer resistance to first-generation clinical FGFR inhibitors such as NVP-BGJ398 and AZD4547. Because of the conformational flexibility of the reactive acrylamide substituent, FIIN-3 has the unprecedented ability to inhibit both the EGF receptor (EGFR) and FGFR covalently by targeting two distinct cysteine residues. We report the cocrystal structure of FGFR4 with FIIN-2, which unexpectedly exhibits a "DFG-out" covalent binding mode. The structural basis for dual FGFR and EGFR targeting by FIIN3 also is illustrated by crystal structures of FIIN-3 bound with FGFR4 V550L and EGFR L858R. These results have important implications for the design of covalent FGFR inhibitors that can overcome clinical resistance and provide the first example, to our knowledge, of a kinase inhibitor that covalently targets cysteines located in different positions within the ATP-binding pocket.
AB - The human FGF receptors (FGFRs) play critical roles in various human cancers, and several FGFR inhibitors are currently under clinical investigation. Resistance usually results from selection for mutant kinases that are impervious to the action of the drug or from up-regulation of compensatory signaling pathways. Preclinical studies have demonstrated that resistance to FGFR inhibitors can be acquired through mutations in the FGFR gatekeeper residue, as clinically observed for FGFR4 in embryonal rhabdomyosarcoma and neuroendocrine breast carcinomas. Here we report on the use of a structure-based drug design to develop two selective, next-generation covalent FGFR inhibitors, the FGFR irreversible inhibitors 2 (FIIN-2) and 3 (FIIN-3). To our knowledge, FIIN-2 and FIIN-3 are the first inhibitors that can potently inhibit the proliferation of cells dependent upon the gatekeeper mutants of FGFR1 or FGFR2, which confer resistance to first-generation clinical FGFR inhibitors such as NVP-BGJ398 and AZD4547. Because of the conformational flexibility of the reactive acrylamide substituent, FIIN-3 has the unprecedented ability to inhibit both the EGF receptor (EGFR) and FGFR covalently by targeting two distinct cysteine residues. We report the cocrystal structure of FGFR4 with FIIN-2, which unexpectedly exhibits a "DFG-out" covalent binding mode. The structural basis for dual FGFR and EGFR targeting by FIIN3 also is illustrated by crystal structures of FIIN-3 bound with FGFR4 V550L and EGFR L858R. These results have important implications for the design of covalent FGFR inhibitors that can overcome clinical resistance and provide the first example, to our knowledge, of a kinase inhibitor that covalently targets cysteines located in different positions within the ATP-binding pocket.
KW - Cancer drug resistance
KW - Drug discovery
KW - Kinase inhibitor
KW - Structure-based drug design
UR - http://www.scopus.com/inward/record.url?scp=84909594628&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84909594628&partnerID=8YFLogxK
U2 - 10.1073/pnas.1403438111
DO - 10.1073/pnas.1403438111
M3 - Article
VL - 111
SP - E4869-E4877
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
SN - 0027-8424
IS - 45
ER -