PDBsum entry 2rfs

Transferase

PDB id: 2rfs

Contents

Protein chain

264 a.a.

Ligands

AM8

Waters ×135

References listed in PDB file

Key reference

Title

C-Met inhibitors with novel binding mode show activity against several hereditary papillary renal cell carcinoma-Related mutations.

Authors

S.F.Bellon, P.Kaplan-Lefko, Y.Yang, Y.Zhang, J.Moriguchi, K.Rex, C.W.Johnson, P.E.Rose, A.M.Long, A.B.O'Connor, Y.Gu, A.Coxon, T.S.Kim, A.Tasker, T.L.Burgess, I.Dussault.

Ref.

J Biol Chem, 2008, 283, 2675-2683. [DOI no: 10.1074/jbc.M705774200]

PubMed id

18055465

Abstract

c-Met is a receptor tyrosine kinase often deregulated in human cancers, thus making it an attractive drug target. One mechanism by which c-Met deregulation leads to cancer is through gain-of-function mutations. Therefore, small molecules capable of targeting these mutations could offer therapeutic benefits for affected patients. SU11274 was recently described and reported to inhibit the activity of the wild-type and some mutant forms of c-Met, whereas other mutants are resistant to inhibition. We identified a novel series of c-Met small molecule inhibitors that are active against multiple mutants previously identified in hereditary papillary renal cell carcinoma patients. AM7 is active against wild-type c-Met as well as several mutants, inhibits c-Met-mediated signaling in MKN-45 and U-87 MG cells, and inhibits tumor growth in these two models grown as xenografts. The crystal structures of AM7 and SU11274 bound to unphosphorylated c-Met have been determined. The AM7 structure reveals a novel binding mode compared with other published c-Met inhibitors and SU11274. The molecule binds the kinase linker and then extends into a new hydrophobic binding site. This binding site is created by a significant movement of the C-helix and so represents an inactive conformation of the c-Met kinase. Thus, our results demonstrate that it is possible to identify and design inhibitors that will likely be active against mutants found in different cancers.

Figure 5.
FIGURE 5. X-ray structure of AM7 bound to c-Met. A, overview of complex. AM7 is shown in yellow, activating c-Met mutations are shown in pink, and side chains of interest are colored blue. Activating mutation M1250T is below the field of view and so is not shown. At its closest approach to AM7 it is still 18 Å removed from AM7. Activating mutations D1228H and Y1230H are located in the activation loop, which is disordered in this structure. B, experimental f[o] - f[c] electron density contoured around AM7 at 2.5 .

Figure 6.
FIGURE 6. Comparison of AM7 binding to c-Met with activated Lck. AM7 does not clash with the activation loop of activated Lck, but it does clash with the active conformation of the Lck C-helix. All of the protein backbone atoms from the two crystal structures were used to guide the alignment, but only the Lck protein is shown in the figure. AM7 is colored yellow, and the Lck protein is colored blue.

The above figures are reprinted by permission from the ASBMB: J Biol Chem (2008, 283, 2675-2683) copyright 2008.