c-Met inhibitors with novel binding mode show activity against several hereditary papillary renal cell carcinoma-related mutations.
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.
Bellon
Steven F
SF
Department of Molecular Structure, Amgen Inc., Thousand Oaks, CA 91320, USA.
Kaplan-Lefko
Paula
P
Yang
Yajing
Y
Zhang
Yihong
Y
Moriguchi
Jodi
J
Rex
Karen
K
Johnson
Carol W
CW
Rose
Paul E
PE
Long
Alexander M
AM
O'Connor
Anne B
AB
Gu
Yan
Y
Coxon
Angela
A
Kim
Tae-Seong
TS
Tasker
Andrew
A
Burgess
Teresa L
TL
Dussault
Isabelle
I
D000818:Animals; D001665:Binding Sites; D002292:Carcinoma, Renal Cell / Q000188:drug therapy / Q000201:enzymology* / Q000235:genetics* / Q000473:pathology; D045744:Cell Line, Tumor; D018360:Crystallography, X-Ray; D015195:Drug Design; D005260:Female; D006801:Humans; D007211:Indoles / Q000494:pharmacology; D007680:Kidney Neoplasms / Q000188:drug therapy / Q000201:enzymology* / Q000235:genetics* / Q000473:pathology; D051379:Mice; D008819:Mice, Nude; D008958:Models, Molecular; D009154:Mutation; D009368:Neoplasm Transplantation; D010879:Piperazines / Q000494:pharmacology; D011487:Protein Conformation; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000494:pharmacology; D019859:Proto-Oncogene Proteins c-met / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics*; D011744:Pyrimidinones / Q000737:chemistry / Q000494:pharmacology; D011804:Quinolines / Q000737:chemistry / Q000494:pharmacology; D011993:Recombinant Fusion Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000235:genetics; D013449:Sulfonamides / Q000494:pharmacology; D014183:Transplantation, Heterologous
C478479:((3Z)-N-(3-chlorophenyl)-3-((3,5-dimethyl-4-((4-methylpiperazin-1-yl)carbonyl)-1H-pyrrol-2-yl)methylene)-N-methyl-2-oxo-2,3-dihydro-1H-indole-5-sulfonamide); C558303:5-(3-fluoro-4-((6-(methyloxy)-7-((3-(4-morpholinyl)propyl)oxy)-4-quinolinyl)oxy)phenyl)-3-methyl-2-(phenylmethyl)-4(3H)pyrimidinone; D007211:Indoles; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011744:Pyrimidinones; D011804:Quinolines; D011993:Recombinant Fusion Proteins; D013449:Sulfonamides; D019859:Proto-Oncogene Proteins c-met