Delving into the Latest Updates on Fisogatinib with Synapse

Overview

Basic Info

Drug Type

Small molecule drug

Synonyms

Fisogatinib (USAN/INN)

+ [5]

Target

FGFR4

Mechanism

FGFR4 antagonists(Fibroblast growth factor receptor 4 antagonists)

Therapeutic Areas

NeoplasmsDigestive System Disorders

Active Indication

Hepatocellular CarcinomaColorectal Cancer

Inactive Indication

Bile Duct Neoplasms

Originator Organization

Blueprint Medicines Corp.

Active Organization

Cornerstone Pharmaceutical Co., Ltd

Blueprint Medicines Corp.

People's Liberation Army Air Force Military Medical University

Inactive Organization-

Drug Highest PhasePhase 1

First Approval Date-

Regulation-

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Structure/Sequence

Molecular FormulaC24H24Cl2N4O4

InChIKeyMGZKYOAQVGSSGC-DLBZAZTESA-N

CAS Registry1707289-21-1

This is a Phase 1, open-label, first-in-human (FIH) study designed to evaluate the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD), and preliminary antineoplastic activity of fisogatinib (formerly known as BLU- 554) administered orally in patients with FGF19 IHC+ hepatocellular carcinoma (HCC). The study consists of 3 parts, a dose-escalation part (Part 1), an expansion part (Part 2) exploring a once daily (qd) dosing schedule at the recommended Phase 2 dose (RP2D), and a Part 3 expansion of the qd dosing schedule at the RP2D in TKI naive patients.

Start Date31 Jul 2015

Sponsor / Collaborator

Blueprint Medicines Corp.

100 Clinical Results associated with Fisogatinib

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100 Translational Medicine associated with Fisogatinib

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100 Patents (Medical) associated with Fisogatinib

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17

Literatures (Medical) associated with Fisogatinib

01 Dec 2024·Cancer Medicine

Fibroblast Growth Factor Receptor 4 Promotes Triple‐Negative Breast Cancer Progression via Regulating Fatty Acid Metabolism Through the AKT/RYR2 Signaling

Article

Author: Ye, Jinhui ; Quan, Qiang ; Zhang, Jinhui ; Fan, Yidan ; Ye, Feng ; Song, Cailu ; Wu, Song ; Zhao, Jianfu ; Tang, Hailin ; Cao, Huijiao

ABSTRACTBackgroundTriple‐negative breast cancer (TNBC) is the most aggressive subtype of breast cancer. Previous studies have found that fibroblast growth factor receptor 4 (FGFR4) plays a crucial role in tumor development and metastasis. However, the potential role and underlying mechanisms of FGFR4 in the progression of TNBC remain unclear.MethodsStatistical analysis of FGFR4 expression data in public databases was used to reveal its role in TNBC. qRT‐PCR was used to detect FGFR4 expression levels. The impact of FGFR4 level changes on TNBC cell proliferation was assessed using CCK‐8 and colony formation assays, while Transwell invasion assays and JC‐1 staining were employed to analyze the effects of FGFR4 level changes on the invasiveness and survival capability of TNBC cells. Differentially expressed genes were subjected to Gene Ontology, KEGG, and GSEA enrichment analyses to identify associated signaling pathways. Additionally, Oil Red O staining, fatty acid metabolite detection, and Western blot analysis were used to investigate the impact of FGFR4 and its inhibitor fisogatinib, as well as the AKT activator SC79, on the metabolic reprogramming of fatty acids in TNBC cells.ResultsFGFR4 was found to be upregulated in breast cancer and correlated with poorer patient outcomes. Inhibition of FGFR4 resulted in reduced cell growth and invasion in TNBC cells. It also led to increased lipid accumulation, upregulated lipid biosynthesis‐related genes, and downregulated lipolysis‐related genes. Mechanistically, FGFR4 inhibition suppressed the activation of the AKT/RYR2 signaling pathway. Reactivating the AKT pathway reversed the suppressive effects of FGFR4 inhibition on TNBC progression.ConclusionDysregulated FGFR4 activates the AKT/RYR2 axis, leading to tumor proliferation, invasion, and altered lipid metabolism in TNBC. FGFR4 inhibition could potentially serve as a novel therapeutic strategy for TNBC treatment.

01 Nov 2024·Gene

Genome-wide identification of Fgfr genes and function analysis of Fgfr4 in myoblasts differentiation of Lateolabrax maculatus

Article

Author: Zhang, Kaiqiang ; Wang, Lingyu ; Wen, Haishen ; Qi, Xin ; Li, Yun ; Dong, Ximeng ; Li, Hao

Fibroblast growth factor receptors (Fgfrs) are involved in cell proliferation, differentiation, and migration via complex signaling pathways in different tissues. Our previous studies showed that fibroblast growth factor receptor 4 (fgfr4) was detected in the most significant quantitative trait loci (QTL) for growth traits. However, studies focusing on the function of fgfr4 on the growth of bony fish are still limited. In this study, we identified seven fgfr genes in spotted sea bass (Lateolabrax maculatus) genome, namely fgfr1a, fgfr1b, fgfr2, fgfr3, fgfr4, fgfr5a, and fgfr5b. Phylogenetic analysis, syntenic analysis and gene structure analysis were conducted to further support the accuracy of our annotation and classification results. Additionally, fgfr4 showed the highest expression levels among fgfrs during the proliferation and differentiation stages of spotted sea bass myoblasts. To further study the function of fgfr4 in myogenesis, dual-fluorescence in situ hybridization (ISH) assay was conducted, and the results showed co-localization of fgfr4 with marker gene of skeletal muscle satellite cells. By treating differentiating myoblasts cultured in vitro with BLU-554, the mRNA expressions of myogenin (myog) and the numbers of myotubes formed by myoblasts increased significantly compared to negative control group. These results indicated that Fgfr4 inhibits the differentiation of myoblasts in spotted sea bass. Our findings contributed to filling a research gap on fgfr4 in bony fish myogenesis and the theoretical understanding of growth trait regulation of spotted sea bass.

23 May 2024·Journal of Medicinal Chemistry

Discovery of 2,6-Naphthyridine Analogues as Selective FGFR4 Inhibitors for Hepatocellular Carcinoma

Article

Author: Singh, Pargat ; Kim, Jisook ; Oh, Heesook ; Ha, Tae Hee ; Jung, Seung Hyun ; Ahn, Young Gil ; Nam, Gibeom ; Moon, Kyeongwon ; Kim, In Su

Hepatocellular carcinoma (HCC) is the most common type of liver cancer and is responsible for 90% of cases. Approximately 30% of patients diagnosed with HCC are identified as displaying an aberrant expression of fibroblast growth factor 19 (FGF19)-fibroblast growth factor receptor 4 (FGFR4) as an oncogenic-driver pathway. Therefore, the control of the FGF19-FGFR4 signaling pathway with selective FGFR4 inhibitors can be a promising therapy for the treatment of HCC. We herein disclose the design and synthesis of novel FGFR4 inhibitors containing a 2,6-naphthyridine scaffold. Compound 11 displayed a nanomolar potency against Huh7 cell lines and high selectivity over FGFR1-3 that were comparable to that of fisogatinib (8) as a reference standard. Additionally, compound 11 demonstrated remarkable antitumor efficacy in the Huh7 and Hep3B HCC xenograft mouse model. Moreover, bioluminescence imaging experiments with the orthotopic mouse model support that compound 11 can be considered a promising candidate for treating HCC.

100 Deals associated with Fisogatinib

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External Link

KEGG	Wiki	ATC	Drug Bank
D11737	-	-	DB16167

R&D Status

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Hepatocellular Carcinoma	Phase 3	CN	Cornerstone Pharmaceutical Co., Ltd	27 Nov 2019
Bile Duct Neoplasms	Phase 3	US	Blueprint Medicines Corp.	-
Colorectal Cancer	Preclinical	CN	People's Liberation Army Air Force Military Medical University	22 Feb 2023

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Clinical Result

Indication

Phase

Evaluation

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT02508467 (Pubmed) Manual	Phase 1	FGFR4 positive Neoplasms FGF19 Positive	115	Fisogatinib (FGF19-positive)	(dvugzxssjs) = most adverse events were manageable, grade 1/2 gastrointestinal events, primarily diarrhea, nausea, and vomiting. ytzwjolrqr (eqnhfhrdyj )	Positive	01 Dec 2019
				Fisogatinib (FGF19-negative)