BLU 9931 / Blueprint Medicines, Roche - LARVOL DELTA

High Dietary Phosphate Intake Induces Hypertension and Sympathetic Overactivation Through Central Fibroblast Growth Factor Receptor Signaling. (PubMed, Circulation) - "ICV injection of BLU9931, a relatively selective FGFR4 inhibitor, also decreased the responses in HP rats only (∆RSNA=112±70 versus 65±46% [P=0.006] and ∆MAP=41±14 versus 20±14 mm Hg [P<0.0001] before versus after ICV injection). However, ICV administration of AZD4547, a FGFR1-3 inhibitor, and C-terminal FGF23 peptide, a competitive inhibitor of FGF23/FGFR/α-Klotho complex formation, did not alter the responses in either NP or HP animals. Our data reveal a novel pathophysiologic paradigm of high-phosphate diet-induced sympathoexcitation and hypertension by FGF23 crossing into the brain, possibly acting through FGFR4."

Journal • Anesthesia • Cardiovascular • Hypertension • FGF23 • FGFR • FGFR4

Beta klotho as a regulator of liver cancer cell proliferation and liver cancer development (EASL 2025) - "Similar to previous studies, specific inhibition of FGFR4 using BLU9931 did not affect cell proliferation... By inducing a lentiviral shRNA-mediated knockdown of KLB in Hep3B cells, we observed a decrease in cell proliferation upon a loss of KLB, suggesting that KLB can regulate liver cancer cell proliferation. Moreover, we identified that loss of KLB in Hep3B cells resulted in a dysregulation of cancer-related pathways, indicating a role for KLB in liver cancer cell development."

Hepatocellular Cancer • Hepatology • Liver Cancer • Oncology • Solid Tumor • FGF19 • FGFR1 • FGFR4

Fibroblast Growth Factor 23 (FGF-23) Inhibits Gasdermin E (GSDME)-Mediated Pyroptosis via Autophagy in Folic Acid-Induced AKI (KIDNEY WEEK 2024) - "The FGFR4 specific inhibitor BLU9931 showed similar results... Our study elucidated the protective role of FGF23 in AKI and clarified its underlying mechanism by targeting GSDME-mediated pyroptosis through autophagy."

Acute Kidney Injury • Nephrology • Renal Disease • CASP3 • FGF23 • FGFR4 • GSDME

Probing Dual Covalent Irreversible Inhibition of EGFR/FGFR4 by Electrophilic-Based Natural Compounds to Overcome Resistance and Enhance Combination Therapeutic Potentials and Management of Hepatocellular Carcinoma (HCC). (PubMed, Protein J) - "Covalent docking and covalent molecular dynamics (MM/MDcov) simulations combined with thermodynamic binding free energy calculations were performed, and the results were compared against known potent and selective covalent EGFR and FGFR4 inhibitors with available X-ray crystal structures, Afatinib and BLU9931, respectively. The findings of this study identified that curcumin, syringolin A and andrographolide-but not eupalmerin acetate or deoxyelephantopin -could be viable dual EGFR and FGFR4 covalent irreversible inhibitors and could be implemented in HCC combination therapy protocols alone or in conjunction with other chemotherapeutic agents. Investigations of this study conclusively indicate dual blockade of EGFR and FGFR4 may be a promising future therapeutic strategy for enhanced management of HCC."

Combination therapy • Journal • Gastrointestinal Cancer • Hepatocellular Cancer • Hepatology • Liver Cancer • Oncology • Solid Tumor • EGFR • FGF19 • FGFR4

FGF23-Mediated Hypertension via Augmented Calcium Entry in Vascular Smooth Muscle Cells (ERA-EDTA 2024) - "To elucidate the in vitro pro-hypertensive mechanisms of FGF23, studies were conducted with the administration of inhibitors targeting FGF Receptors 1-3 (AZD4547, 150 nM), FGF Receptor-4 (BLU9931, 10 nM), and Erk1/2 phosphorylation (PD98059, 10 M)...The addition of Thapsigargin in a Ca2+-free culture medium to VSMCs incubated with recombinant FGF23 for 9 days led to increased Ca2+ efflux from endoplasmic reticulum... Elevated levels of FGF23 directly enhanced calcium entry in VSMCs. This effect is mediated by FGFR1-3 receptors, Erk1/2 phosphorylation, and the upregulation of related protein to cell contraction such as SERCA2a, PKD1 or AGTR1. These modifications could be responsible of FGF23-associated hypertension in the experimental model."

Cardiovascular • Hypertension • FGF23 • FGFR4 • PKD1 • PRKD1 • STIM1

Cellular Senescence in the Cystic Fibrosis Bronchial Epithelium Is Inhibited by Fibroblast Growth Factor Receptor Blockade (ATS 2023) - "Cells were treated with AZD4547 (FGFR1-3 inhibitor) or BLU9931 (FGFR4 inhibitor) at 0.1uM for 24 hours then collected for RNA, protein and SA-βgal staining. Cellular senescence markers are increased in both in vitro and in vivo models of CF. Our data suggests that FGFR inhibition significantly decreases expression of cellular senescence markers in CF via p38 signaling providing evidence that FGFRs may be an amenable target for future “anti-aging” therapies in CF airway disease."

IO biomarker • Cystic Fibrosis • Fibrosis • Genetic Disorders • Immunology • Infectious Disease • Inflammation • Pulmonary Disease • Respiratory Diseases • BCL2 • BCL2L1 • CDKN1A • CXCL8 • FGFR • FGFR4 • IL1B • IL6

HMGA1 induces FGF19 to drive pancreatic carcinogenesis and stroma formation. (PubMed, J Clin Invest) - "Surprisingly, disrupting FGF19 via gene silencing or the FGFR4 inhibitor BLU9931 recapitulates most phenotypes observed with HMGA1 deficiency, decreasing tumor growth and formation of a desmoplastic stroma in mouse models of PDAC. In human PDAC, overexpression of HMGA1 and FGF19 defines a subset of tumors with extremely poor outcomes. Our results reveal what we believe is a new paradigm whereby HMGA1 and FGF19 drive tumor progression and stroma formation, thus illuminating FGF19 as a rational therapeutic target for a molecularly defined PDAC subtype."

Journal • Stroma • Fibrosis • Gastrointestinal Cancer • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • FGF19 • FGFR4 • HMGA1

The genomic landscape of male breast cancers using the Oncomine Comprehensive Assay for actionable mutations (SABCS 2019) - P2; "Gene amplifications were most frequently detected in MYC (24.5%), FGFR1 (14.8%), CCND1 (12%), FGF3 (9.7%), FGF19 (9.7%), MDM2 (6.5%), CDK4 (1.4%), FGFR3, MDM4, ERBB2 (0.9% each), and FLT3, AR, MYCL, CDK6, IGF1R, FGFR4, KRAS, AKT3 and ESR1 (0.5% each)... In this targeted sequencing study of the largest series of male BCas to our knowledge, we have revealed that PIK3CA continues to be a frequently altered gene in both male and female BCas. However, there is an enrichment of mutations in genes related to DNA repair in male BCs. Interestingly, while MYC is commonly amplified in female BCa, a higher frequency of amplified cases were seen in male BCas, in contrast to female BCas."

AKT3 • ATR • BRCA2 • CCND1 • CDK4 • CDK6 • CHEK1 • ER • FGF19 • FGFR1 • FGFR3 • FGFR4 • FLT3 • GATA3 • HER2 • IGF1R • KRAS • MDM2 • MDM4 • NOTCH2 • PIK3CA • PTEN • TP53

Identification of resistance mechanisms to FGFR4 targeted therapy in hepatocellular carcinoma (AACR-NCI-EORTC 2019) - P1; "In this study, we validate for the first time a driver of disease in the FGF19 expressing subset of HCC through the identification of Fisogatinib resistance mutations in FGFR4. Using a gatekeeper-agnostic pan-FGFR inhibitor we show, in preclinical models, continued FGF19/FGFR4 pathway dependence. These results validate FGF19/FGFR4 as an oncogenic driver and inform the profile of potential next-generation inhibitors designed to facilitate improved patient outcomes."

Fibroblast growth factor receptor type 4 as a potential therapeutic target in clear cell renal cell carcinoma. (PubMed, BMC Cancer) - "FGFR4 contributes to ccRCC cell proliferation and survival following FGFR4 amplification, making it a potential therapeutic target for ccRCC."

Journal • Clear Cell Renal Cell Carcinoma • Genito-urinary Cancer • Oncology • Renal Cell Carcinoma • Solid Tumor • FGFR • FGFR4

Strategies to inhibit FGFR4 V550L-driven rhabdomyosarcoma. (PubMed, Br J Cancer) - "Our results pave the way for precision medicine approaches against FGFR4 V550L-driven RMS."

Journal • Oncology • Pediatrics • Rhabdomyosarcoma • Sarcoma • Solid Tumor • FGFR4 • PAX3

FGF19 Is Coamplified With CCND1 to Promote Proliferation in Lung Squamous Cell Carcinoma and Their Combined Inhibition Shows Improved Efficacy. (PubMed, Front Oncol) - "Furthermore, the combination treatment of the FGFR4 inhibitor BLU9931 and the CDK4/6 inhibitor palbociclib potentiated the growth inhibition and arrested cells in G1 phase. In vivo, co-targeting FGFR4 and CDK4/6 also showed marked inhibition of tumor growth than single agent treatment. These findings further elucidate the oncogenic role of FGF19 in LUSC and provide insights into how the co-amplification of neighboring genes synergistically function to promote cancer growth, and combined inhibition against both FGF19 and CCND1 is more effective."

Journal • Eye Cancer • Non Small Cell Lung Cancer • Oncology • Retinal Disorders • Retinoblastoma • Solid Tumor • Squamous Cell Carcinoma • CCND1 • FGF19 • FGFR4

6-Amino-2,4,5-trimethylpyridin-3-ol and 2-amino-4,6-dimethylpyrimidin-5-ol derivatives as selective fibroblast growth factor receptor 4 inhibitors: design, synthesis, molecular docking, and anti-hepatocellular carcinoma efficacy evaluation. (PubMed, J Enzyme Inhib Med Chem) - "In vivo anti-tumour activity of compound 6O against Hep3B-xenografted CAM tumour model was almost similar to BLU9931. Overall, compound 6O, a novel derivative of aminodimethylpyrimidinol, was a selective FGFR4 kinase inhibitor blocking HCC tumour growth."

Journal • Gastrointestinal Cancer • Hepatocellular Cancer • Hepatology • Oncology • Solid Tumor • FGFR1 • FGFR4

Design, synthesis, and biological evaluation of quinazoline derivatives with covalent reversible warheads as potential FGFR4 inhibitors. (PubMed, Bioorg Chem) - "Based on BLU9931, we designed and synthesized a series of phenylquinazoline derivatives as novel inhibitors of FGFR4 through the covalent reversible strategy...Cellular mechanism studies demonstrated that compound C3 induced apoptosis via the FGFR4 signaling pathway blockage. Further mechanism study showed that C3 has the reversible covalent binding capacity, could be used as a reference for the development of novel FGFR4 covalent reversible inhibitors."

Journal • Gastrointestinal Cancer • Hepatocellular Cancer • Oncology • Solid Tumor • FGFR4

Anti-cancer effects of 3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one derivatives on hepatocellular carcinoma harboring FGFR4 activation. (PubMed, Neoplasia) - "Especially, SIJ1263 is 80-fold more potent (GI = 24 nM) on TEL-FGFR4 V550E Ba/F3 cells than BLU9931, which suggests that SIJ1263 would be effective for overriding drug resistance...It is worth noting that SIJ1263 is superior to GNF-7 with regards to the fact that activities of SIJ1263 are higher than those of GNF-7 in all assays performed in this study. Collectively, this study provides insight into designing highly potent FGFR4 inhibitors capable of potentially overcoming drug-resistance for the treatment of HCC patients."

Journal • Gastrointestinal Cancer • Hepatocellular Cancer • Oncology • Solid Tumor • FGFR4

Design, synthesis and biological evaluation of quinazoline derivatives as potent and selective FGFR4 inhibitors. (PubMed, Eur J Med Chem) - "It is assumed that the first FGFR4 inhibitor BLU9931 did not enter clinical studies, presumably due to its rapid metabolism in liver microsomes...Cellular mechanistic studies demonstrated that 35a induced apoptosis via the FGFR4 signaling pathway blockage. In addition, the computational simulation revealed the possible binding mode to FGFR4 protein, which provides a plausible explanation of high potent and metabolic stability."

Journal • Gastrointestinal Cancer • Hepatocellular Cancer • Oncology • Solid Tumor • FGF19 • FGFR4

Evaluation of FGFR targeting in breast cancer through interrogation of patient-derived models. (PubMed, Breast Cancer Res) - "This work highlights how patient-derived models of human breast cancer provide powerful platforms for therapeutic target identification and analysis of drug action, and also the potential of specific FGFRs, including FGFR4, as targets for precision treatment."

Clinical • Journal • Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • FGFR • FGFR1 • FGFR2 • FGFR4

Aberrant FGFR4 signaling worsens nonalcoholic steatohepatitis in FGF21KO mice. (PubMed, Int J Biol Sci) - "In in vitro studies, blockage of FGFR4 by BLU9931 treatment attenuated the lipid accumulation, up-regulated cyclin D1, and epithelial-mesenchymal transition (EMT) in the hepatocytes. The increased FGF15 in NASH-FGF21KO mice could not substitute for FGF21 to compensate its lipid metabolic benefits thereby to prevent NASH development. Up-regulated FGFR4 signaling in NASH-FGF21KO mice coupled to proliferation and EMT events which were widely accepted to be associated with carcinogenic transformation."

Journal • Preclinical • Fibrosis • Gastrointestinal Cancer • Hepatocellular Cancer • Hepatology • Immunology • Non-alcoholic Fatty Liver Disease • Non-alcoholic Steatohepatitis • Oncology • Solid Tumor • CCND1 • FGF21 • FGFR4

FGF19 and FGFR4 promotes the progression of gallbladder carcinoma in an autocrine pathway dependent on GPBAR1-cAMP-EGR1 axis. (PubMed, Oncogene) - "BLU9931 inhibited FGFR4 and attenuated its oncogenic effects in GBC cell line...Co-expression of FGF19 and FGFR4 was a sensitive and unfavorable prognostic marker. GBC cells secreted FGF19 and facilitated progression by activating FGFR4 with bile as a potential carrier in an autocrine pathway."

Journal • Gallbladder Cancer • Gastroenterology • Gastrointestinal Cancer • Hepatology • Oncology • Solid Tumor • EGR1 • FGF19 • FGFR1 • FGFR4

[VIRTUAL] FGFR4 inhibitor BLU9931 induces cellular senescence in pancreatic ductal adenocarcinoma cell lines promoting sensitivity to senolytic therapy (AACR 2021) - "We demonstrated that inhibition of signal transduction pathways through the ERK, AKT, and STAT3 pathways by BLU9931 inhibited PDAC cell proliferation and invasion, in part by downregulating MT1-MMP expression in autocrine/paracrine FGF19/FGFR4 signaling-positive PDAC cells. Furthermore, downregulation of SIRT1 and SIRT6 by BLU9931 may have contributed to senolysis in these cells. Thus, we propose that BLU9931 may be a promising drug for the treatment of FGFR4-positive PDAC."

Preclinical • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • FGF19 • FGFR4 • SIRT1 • SIRT6

Src is essential for the endosomal delivery of the FGFR4 signaling complex in hepatocellular carcinoma. (PubMed, J Transl Med) - "We found that Src is essential for the endosomal delivery of the FGFR4 signaling complex in HCC. Our findings provide a scientific rationale for repurposing Src inhibitors for the treatment of HCCs in which the FGFR4 pathway is activated."

Journal • Gastrointestinal Cancer • Hepatocellular Cancer • Hepatology • Oncology • Solid Tumor • FGF19 • FGFR1 • FGFR2 • FGFR4 • STAT3

Excessive fibroblast growth factor 23 promotes renal fibrosis in mice with type 2 cardiorenal syndrome. (PubMed, Aging (Albany NY)) - "These changes were attenuated by FGFR4 blockade with BLU9931 or β-catenin blockade with IGC001. We concluded that FGF23 promotes CRS-induced renal fibrosis mediated by partly activating FGFR4/β-catenin signaling pathway."

Journal • Cardiovascular • Fibrosis • Immunology • Myocardial Infarction • Nephrology • Renal Disease • FGF • FGF23 • FGFR4 • VIM

Discoveryof BLU-554: A potent and highlyselective covalent FGFR4 inhibitor for targeted treatment of advanced hepatocellular carcinoma (AACR 2018) - "There is no abstract associated with this presentation."

Hepatocellular Cancer

ED08 - From Chemistry to the Clinic: Part 2 - Lead Optimization in Cancer Drug Discovery and Development, Multifactorial Optimization from Early Hits to Drug Candidates (AACR 2018) - "These cover four very different classes of protein targets and distinct chemotypes. They are: new generation of SERDs from Genentech, covalent FGFR4 from Blueprint Medicine, splicesome modulator from H3 Biomedicine and new chemotypes for IDO inhibitors."

Oncology

Pyrrolo[2,3-b]pyridine-3-one derivatives as novel fibroblast growth factor receptor 4 inhibitors for the treatment of hepatocellular carcinoma. (PubMed, Bioorg Med Chem) - "Compound 25 exhibited good in vitro human liver microsomal stability with the half-life of 62.0 min, which was more stable than BLU9931 (46.7 min). But the in vivo pharmacokinetic results showed that the oral bioavailability was only 6.65%, which needs to be improved in the next work. These results showed that compound 25 might be an effective lead compound for further investigation to treat the hepatocellular carcinoma."

Journal • Gastrointestinal Cancer • Hepatocellular Cancer • Hepatology • Liver Cancer • Oncology • Solid Tumor