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Science 9 May 1997:
Vol. 276. no. 5314, pp. 955 - 960
DOI: 10.1126/science.276.5314.955
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Reports

Structures of the Tyrosine Kinase Domain of Fibroblast Growth Factor Receptor in Complex with Inhibitors

Moosa Mohammadi, Gerald McMahon, Li Sun, Cho Tang, Peter Hirth, Brian K. Yeh, Stevan R. Hubbard, * Joseph Schlessinger *

A new class of protein tyrosine kinase inhibitors was identified that is based on an oxindole core (indolinones). Two compounds from this class inhibited the kinase activity of fibroblast growth factor receptor 1 (FGFR1) and showed differential specificity toward other receptor tyrosine kinases. Crystal structures of the tyrosine kinase domain of FGFR1 in complex with the two compounds were determined. The oxindole occupies the site in which the adenine of adenosine triphosphate binds, whereas the moieties that extend from the oxindole contact residues in the hinge region between the two kinase lobes. The more specific inhibitor of FGFR1 induces a conformational change in the nucleotide-binding loop. This structural information will facilitate the design of new inhibitors for use in the treatment of cancer and other diseases in which cell signaling by tyrosine kinases plays a crucial role in disease pathogenesis.

M. Mohammadi, B. K. Yeh, J. Schlessinger, Department of Pharmacology, New York University Medical Center, New York, NY 10016, USA.
G. McMahon, L. Sun, C. Tang, P. Hirth, SUGEN, Redwood City, CA 94063, USA.
S. R. Hubbard, Skirball Institute of Biomolecular Medicine and Department of Pharmacology, New York University Medical Center, New York, NY 10016, USA.
*   To whom correspondence should be addressed.

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Screening of FGF target genes in Xenopus by microarray: temporal dissection of the signalling pathway using a chemical inhibitor.
H. A. Chung, J. Hyodo-Miura, A. Kitayama, C. Terasaka, T. Nagamune, and N. Ueno (2004)
Genes Cells 9, 749-761
   Abstract »    Full Text »    PDF »
Developmental Regulation of Gonadotropin-Releasing Hormone Neurons by Fibroblast Growth Factor Signaling.
J. C. Gill, S. M. Moenter, and P.-S. Tsai (2004)
Endocrinology 145, 3830-3839
   Abstract »    Full Text »    PDF »
Combinatorial Fgf and Bmp signalling patterns the gastrula ectoderm into prospective neural and epidermal domains.
T. Kudoh, M. L. Concha, C. Houart, I. B. Dawid, and S. W. Wilson (2004)
Development 131, 3581-3592
   Abstract »    Full Text »    PDF »
Fgf3 signaling from the ventral diencephalon is required for early specification and subsequent survival of the zebrafish adenohypophysis.
W. Herzog, C. Sonntag, S. von der Hardt, H. H. Roehl, Z. M. Varga, and M. Hammerschmidt (2004)
Development 131, 3681-3692
   Abstract »    Full Text »    PDF »
Determination of embryonic polarity in a regulative system: evidence for endogenous inhibitors acting sequentially during primitive streak formation in the chick embryo.
F. Bertocchini, I. Skromne, L. Wolpert, and C. D. Stern (2004)
Development 131, 3381-3390
   Abstract »    Full Text »    PDF »
FGF signaling is required for initiation of feather placode development.
M. Mandler and A. Neubuser (2004)
Development 131, 3333-3343
   Abstract »    Full Text »    PDF »
Mouse limb deformity mutations disrupt a global control region within the large regulatory landscape required for Gremlin expression.
A. Zuniga, O. Michos, F. Spitz, A.-P. G. Haramis, L. Panman, A. Galli, K. Vintersten, C. Klasen, W. Mansfield, S. Kuc, et al. (2004)
Genes & Dev. 18, 1553-1564
   Abstract »    Full Text »    PDF »
Fgf signalling controls the dorsoventral patterning of the zebrafish embryo.
M. Furthauer, J. Van Celst, C. Thisse, and B. Thisse (2004)
Development 131, 2853-2864
   Abstract »    Full Text »    PDF »
Tyrosine Phosphorylation of Sprouty Proteins Regulates Their Ability to Inhibit Growth Factor Signaling: A Dual Feedback Loop.
J. M. Mason, D. J. Morrison, B. Bassit, M. Dimri, H. Band, J. D. Licht, and I. Gross (2004)
Mol. Biol. Cell 15, 2176-2188
   Abstract »    Full Text »    PDF »
Protein Kinase Inhibitors: Insights into Drug Design from Structure.
M. E. M. Noble, J. A. Endicott, and L. N. Johnson (2004)
Science 303, 1800-1805
   Abstract »    Full Text »    PDF »
Nodal and Fgf pathways interact through a positive regulatory loop and synergize to maintain mesodermal cell populations.
J. Mathieu, K. Griffin, P. Herbomel, T. Dickmeis, U. Strahle, D. Kimelman, F. M. Rosa, and N. Peyrieras (2004)
Development 131, 629-641
   Abstract »    Full Text »    PDF »
Isthmus-to-midbrain transformation in the absence of midbrain-hindbrain organizer activity.
J. Jaszai, F. Reifers, A. Picker, T. Langenberg, and M. Brand (2003)
Development 130, 6611-6623
   Abstract »    Full Text »    PDF »
Potent and selective inhibitors of the Met [hepatocyte growth factor/scatter factor (HGF/SF) receptor] tyrosine kinase block HGF/SF-induced tumor cell growth and invasion.
X. Wang, P. Le, C. Liang, J. Chan, D. Kiewlich, T. Miller, D. Harris, L. Sun, A. Rice, S. Vasile, et al. (2003)
Mol. Cancer Ther. 2, 1085-1092
   Abstract »    Full Text »    PDF »
Crystal structure of the tyrosine kinase domain of the hepatocyte growth factor receptor c-Met and its complex with the microbial alkaloid K-252a.
N. Schiering, S. Knapp, M. Marconi, M. M. Flocco, J. Cui, R. Perego, L. Rusconi, and C. Cristiani (2003)
PNAS 100, 12654-12659
   Abstract »    Full Text »    PDF »
Engrailed and Fgf8 act synergistically to maintain the boundary between diencephalon and mesencephalon.
S. Scholpp, C. Lohs, and M. Brand (2003)
Development 130, 4881-4893
   Abstract »    Full Text »    PDF »


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