NF449 is a novel inhibitor of fibroblast growth factor receptor 3 (FGFR3) signaling active in chondrocytes and multiple myeloma cells.
The FGFR3 receptor tyrosine kinase represents an attractive target for therapy due to its role in several human disorders, including skeletal dysplasias, multiple myeloma, and cervical and bladder carcinomas. By using molecular library screening, we identified a compound named NF449 with inhibitory activity toward FGFR3 signaling. In cultured chondrocytes and murine limb organ culture, NF449 rescued FGFR3-mediated extracellular matrix loss and growth inhibition, which represent two major cellular phenotypes of aberrant FGFR3 signaling in cartilage. Similarly, NF449 antagonized FGFR3 action in the multiple myeloma cell lines OPM2 and KMS11, as evidenced by NF449-mediated reversal of ERK MAPK activation and transcript accumulation of CCL3 and CCL4 chemokines, both of which are induced by FGFR3 activation. In cell-free kinase assays, NF449 inhibited the kinase activity of both wild type and a disease-associated FGFR3 mutant (K650E) in a fashion that appeared non-competitive with ATP. Our data identify NF449 as a novel antagonist of FGFR3 signaling, useful for FGFR3 inhibition alone or in combination with inhibitors that target the ATP binding site.
Krejci
Pavel
P
Medical Genetics Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA. pavel.krejci@cshs.org
Murakami
Shunichi
S
Prochazkova
Jirina
J
Trantirek
Lukas
L
Chlebova
Katarina
K
Ouyang
Zhufeng
Z
Aklian
Anie
A
Smutny
Jiri
J
Bryja
Vitezslav
V
Kozubik
Alois
A
Wilcox
William R
WR
D000818:Animals; D001557:Benzenesulfonates / Q000494:pharmacology*; D001842:Bone and Bones / Q000166:cytology / Q000187:drug effects; D016466:CHO Cells; D045744:Cell Line, Tumor; D019902:Chondrocytes / Q000187:drug effects / Q000502:physiology*; D006224:Cricetinae; D003412:Cricetulus; D005260:Female; D006801:Humans; D051379:Mice; D009101:Multiple Myeloma / Q000503:physiopathology*; D011494:Protein Kinases / Q000187:drug effects / Q000378:metabolism; D012313:RNA / Q000187:drug effects / Q000235:genetics; D012334:RNA, Neoplasm / Q000187:drug effects / Q000235:genetics; D051498:Receptor, Fibroblast Growth Factor, Type 3 / Q000037:antagonists & inhibitors*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D013431:Sulfates / Q000378:metabolism; D001749:Urinary Bladder Neoplasms / Q000503:physiopathology; D002583:Uterine Cervical Neoplasms / Q000503:physiopathology
C110258:4,4,',4'',4'''-(carbonylbis(imino-5,1,3-benzenetriylbis(carbonylimino)))tetrakis(benzene-1,3-disulfonate); D001557:Benzenesulfonates; D012334:RNA, Neoplasm; D013431:Sulfates; D012313:RNA; D011494:Protein Kinases; D051498:Receptor, Fibroblast Growth Factor, Type 3