ASP5878, a Novel Inhibitor of FGFR1, 2, 3, and 4, Inhibits the Growth of FGF19-Expressing Hepatocellular Carcinoma.
Hepatocellular carcinoma is an aggressive cancer with poor prognosis. Fibroblast growth factor 19, a member of the fibroblast growth factor family, is a ligand for fibroblast growth factor receptor 4. Moreover, it plays a crucial role in the progression of hepatocellular carcinoma. ASP5878 is a novel inhibitor of fibroblast growth factor receptors 1, 2, 3, and 4 that is under development. It inhibits fibroblast growth factor receptor 4 kinase activity with an IC50of 3.5 nmol/L. ASP5878 potently suppressed the growth of the fibroblast growth factor 19-expressing hepatocellular carcinoma cell lines Hep3B2.1-7, HuH-7, and JHH-7. In the Hep3B2.1-7 cell line, ASP5878 inhibited the phosphorylation of fibroblast growth factor receptor 4 and its downstream signaling molecules as well as induced apoptosis. Oral administration of ASP5878 at 3 mg/kg induced sustained tumor regression in a subcutaneous xenograft mouse model using Hep3B2.1-7. In HuH-7, an orthotopic xenograft mouse model, ASP5878 induced complete tumor regression and dramatically extended the survival of the mice. These results suggest that ASP5878 is a potentially effective therapeutic agent for hepatocellular carcinoma patients with tumors expressing fibroblast growth factor 19. Mol Cancer Ther; 16(1); 68-75. ©2016 AACR.
Drug Discovery Research, Astellas Pharma Inc., Ibaraki, Japan. takashi.futami@astellas.com.
Takashi
T
Futami
Drug Discovery Research, Astellas Pharma Inc., Ibaraki, Japan.
Hidetsugu
H
Okada
Drug Discovery Research, Astellas Pharma Inc., Ibaraki, Japan.
Rumi
R
Kihara
Drug Discovery Research, Astellas Pharma Inc., Ibaraki, Japan.
Tatsuya
T
Kawase
Drug Discovery Research, Astellas Pharma Inc., Ibaraki, Japan.
Ayako
A
Nakayama
Drug Discovery Research, Astellas Pharma Inc., Ibaraki, Japan.
Tomoyuki
T
Suzuki
Drug Discovery Research, Astellas Pharma Inc., Ibaraki, Japan.
Minoru
M
Kameda
Drug Discovery Research, Astellas Pharma Inc., Ibaraki, Japan.
Nobuaki
N
Shindoh
Drug Discovery Research, Astellas Pharma Inc., Ibaraki, Japan.
Tadashi
T
Terasaka
Drug Discovery Research, Astellas Pharma Inc., Ibaraki, Japan.
Masaaki
M
Hirano
Drug Discovery Research, Astellas Pharma Inc., Ibaraki, Japan.
Sadao
S
Kuromitsu
D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004195:Disease Models, Animal; D005346:Fibroblast Growth Factors / Q000235:genetics*; D015870:Gene Expression; D006801:Humans; D008113:Liver Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000494:pharmacology; D011720:Pyrazoles / Q000737:chemistry / Q000494:pharmacology*; D011743:Pyrimidines / Q000737:chemistry / Q000494:pharmacology*; D017468:Receptors, Fibroblast Growth Factor / Q000037:antagonists & inhibitors*; D015398:Signal Transduction / Q000187:drug effects; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
C000615784:ASP5878; D000970:Antineoplastic Agents; C117476:FGF19 protein, human; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D011743:Pyrimidines; D017468:Receptors, Fibroblast Growth Factor; D005346:Fibroblast Growth Factors