LY2874455 / Eli Lilly - LARVOL DELTA

Design, synthesis and antitumor activity of a novel FGFR2-selective degrader to overcome resistance of the FGFR2V564F gatekeeper mutation based on a pan-FGFR inhibitor. (PubMed, Eur J Med Chem) - "In this study, we designed several PROTACs with different E3 ligands based on LY2874455...In summary, we identified 28e as a novel selective degrader of FGFR2 with high potency and high potential to overcome resistance to gatekeeper mutation. The discovery of 28e provides new evidence for the strategy of pan-inhibitor-based development of selective degrading agents."

Journal • Oncology • Targeted Protein Degradation • FGFR1 • FGFR2

Selective autophagy of the immunoproteasomes suppresses innate inflammation. (PubMed, Autophagy) - "LY2874455 suppresses inflammation induced by lipopolysaccharide both in vivo and in vitro through autophagic degradation of the immunoproteasomes. In summary, our work uncovers a mechanism of inflammation suppression by autophagy in macrophages."

Journal • Inflammation • Targeted Protein Degradation • SQSTM1

Pharmacological induction of autophagy reduces inflammation in macrophages by degrading immunoproteasome subunits. (PubMed, PLoS Biol) - "In mice, LY2874455 protected against LPS-induced acute lung injury and dextran sulfate sodium (DSS)-induced colitis and caused low levels of proinflammatory cytokines and immunoproteasomes. These findings suggested that selective autophagy of the immunoproteasome was a key regulator of signaling via the innate immune system."

Journal • Acute Lung Injury • Gastroenterology • Gastrointestinal Disorder • Immunology • Inflammation • Respiratory Diseases • SQSTM1

Targeting MET and FGFR in Relapsed or Refractory Acute Myeloid Leukemia: Preclinical, Clinical, and Correlative Studies (ASH 2019) - "Inhibition of HGF-MET signaling with the specific MET kinase inhibitor crizotinib led to a transient therapeutic effect in AML cells; however, resistance rapidly emerged via increased HGF expression due to activation of alternative kinase pathways such as FGFR1 (Kentsis et al., Nat Medicine, 2012). Preliminary clinical data suggest that merestinib is tolerable and the safety of adding dose-escalated LY2874455 is under investigation. Correlative studies to evaluate the significance of changes in HGF production and in STAT3/5 target genes are on-going."

Acute Myelogenous Leukemia • Cardiovascular • Heart Failure • Immunology • Neutropenia • Oncology • Renal Disease • DNMT3A • FGFR1 • FLT3 • HGF • NPM1 • STAT5 • TP53

Targeting MET and FGFR in Relapsed or Refractory Acute Myeloid Leukemia: Preclinical and Clinical Findings, and Signal Transduction Correlates. (PubMed, Clin Cancer Res) - "We provide prospective, preliminary evidence that MET and FGFR are biologically active and safely targetable pathways in AML."

Journal • Preclinical • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • FGFR • HGF

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

LY2874455 and Abemaciclib Reverse FGF3/4/19/CCND1 Amplification Mediated Gefitinib Resistance in NSCLC. (PubMed, Front Pharmacol) - "Mechanistically, FGFs/CCND1 activated the MAPK pathway, which was abolished by the combination drugs. Our study provides a rationale for clinical testing of dual targeting FGFR and CCND1 with LY2874455 and abemaciclib in NSCLC patients who harbored FGF3/4/19/CCND1 amplification."

Journal • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • CCND1 • CDK4 • FGF3

Radiosensitization by the Selective Pan-FGFR Inhibitor LY2874455. (PubMed, Cells) - "This is the first report to show the radiosensitizing effect of a selective pan-FGFR inhibitor. These data suggest the potential efficacy of LY2874455 as a radiosensitizer, warranting clinical validation."

Journal • Oncology • FGFR1

Preclinical evaluation of a panel of FGFR inhibitors for their normal brain and brain tumor distribution (AACR 2022) - "In this study, seven pan-FGFR inhibitors (infigratinib, AZD4547, debio1347, erdafitinib, LY2874455, pemigatinib, and TAS-120) were evaluated for their brain penetration ability employing cassette dosing strategy with an aim to identify the optimal candidates for brain tumor targeting. The predictive parameters of brain penetration calculated based on physico-chemical properties have been estimated and shown not to correlate with the experimentally obtained neuro-pharmacokinetic values. In summary, our study provides comprehensive evaluation of neuro-pharmacokinetic behavior of seven FGFR inhibitors and delivers rationale for selection of most optimal candidates for future investigation in brain tumor clinical trials."

Preclinical • Brain Cancer • Glioblastoma • Oncology • Solid Tumor • ABCB1

Ponatinib, Lestaurtinib and mTOR/PI3K inhibitors are promising repurposing candidates against Entamoeba histolytica. (PubMed, Antimicrob Agents Chemother) - "Additionally, 14 are able to inhibit encystation and 2 (lestaurtinib and LY-2874455) are active against mature cysts. Two classes of compounds are most interesting for further investigations: the Bcr-Abl TK inhibitors, with the ponatinib (EC 0.39) as most potent and mTOR or PI3K inhibitors with 8 compounds in clinical development, of which 4 have nanomolar potency. Overall, these are promising candidates and represent a significant advance for drug development against E. histolytica."

Journal • Gastrointestinal Disorder

Molecular mechanisms of the anti-cancer drug, LY2874455, in overcoming the FGFR4 mutation-based resistance. (PubMed, Sci Rep) - "Interestingly, 6LF binding causes the rigidity of hinge and αD helix regions, which results in overcoming V550L induced resistance. Collectively, the results of this study would be informative for designing more efficient TKIs for more effective targeting of the FGFR signaling pathway."

Journal • Oncology • FGFR4

High-throughput screening of glioma stem-like cells (GSCs) identifies synergistic therapeutic combination of FGFR inhibitor and CDK4/6 inhibitor (AACR 2018) - "Evaluation of drug combination data for synergistic combination identified FGFR inhibitor LY2874455 and CDK4/6 inhibitor LY2835219 as the most effective combinations for multiple drug sets. In addition, Western blotting showed that expression of PDGFR and Notch1 was significantly inhibited by combination treatment. However, this combination failed to show any survival and tumor inhibition benefits in intracranial xenograft mouse models."

PARP Biomarker • Solid Tumor

[VIRTUAL] Drivers of secondary resistance to anti-EGFR therapy in metastatic colorectal cancer (AACR-II 2020) - "Secondary Resistance (SR) evolves in virtually all metastatic colorectal cancers (mCRC) treated with anti-EGFR targeting drugs such as Cetuximab (Cmab). Lastly, when subjecting a Cmab SR pdx model with high endogenous overexpression of FGF13 and FGF19 to a Pan-FGF inhibitor (LY2874455) in combination with Cmab, we observed a conversion of the SR into partial response.Taken together, these results support a role of IGF2 and FGFs as candidate proteins conferring SR in an autocrine fashion in the setting of KRAS wild-type mCRC under chronic anti-EGFR treatment. Importantly, these results also suggest that potential combination therapies of Cmab and an IGF2 or FGF inhibitor could prevent establishment of SR through these pathways and offer new treatment opportunities for patients with SR mCRC."

Colorectal Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor • BRAF • FGF • FGF19 • FGF3 • IGF2 • KRAS • NRAS

A phase I trial of LY2874455, a fibroblast growth factor receptor inhibitor, in patients with advanced cancer (AACR 2014) - Presentation time: Monday, Apr 07, 2014, 8:00 AM -12:00 PM; Abstract #CT215; P1, N=36; "The most common type of treatment-emergent adverse events possibly related to study drug was gastrointestinal (n=2, n=1 Grade 3/4)....There were no reported dose limiting toxicities....Serum phosphorus levels increased following dose with administration of ≥10 mg of LY2874455 but were adequately controlled by phosphate-binding agents."

P1 data • Oncology

A study of LY2874455 in patients with advanced cancer (clinicaltrials.gov) - P1, N=100; Sponsor: Eli Lilly; Recruiting; Completion date: Apr 2013 -> Jun 2014.

Trial completion date • Oncology

Drivers of Secondary Resistance to Anti-Egfr Therapy in Metastatic Colorectal Cancer (DKK 2020) - "Purpose: Secondary Resistance (SR) evolves in virtually all metastatic colorectal cancers (mCRC) treated with anti-EGFR targeting drugs such as Cetuximab (Cmab)...Lastly, when subjecting a Cmab SR pdx model with high endogenous overexpression of FGF13 and FGF19 to a Pan-FGF inhibitor (LY2874455), we observed a conversion of the SR into partial response. Taken together, these results support a role of IGF2 and FGFs as candidate proteins conferring SR in an autocrine fashion in the setting of KRAS wild-type mCRC under chronic anti-EGFR treatment. Importantly, these results also suggest that potential combination therapies of Cmab and an IGF2 or FGF inhibitor could prevent establishment of SR and offer new treatment opportunities for patients with SR mCRC."

Late-breaking abstract • BRAF • FGF19 • FGF3 • IGF2 • KRAS • NRAS

FGFR Signaling as a Candidate Therapeutic Target for Cancers Resistant to Carbon Ion Radiotherapy. (PubMed, Int J Mol Sci) - "Inhibition of FGFR using the clinically available pan-FGFR inhibitor LY2874455 sensitized multiple cancer cell lines to carbon ions at 3 Gy (RBE: relative biological effectiveness), the daily dose prescribed to the patient...Our data indicate the potential usefulness of the analytical pipeline employed in this pilot study to identify targetable mutations associated with resistance to CIRT, and of LY21874455 as a sensitizer for CIRT-resistant cancers. The results warrant validation in larger cohorts."

Journal

The role of fibroblast growth factor receptor (FGFR) protein-tyrosine kinase inhibitors in the treatment of cancers including those of the urinary bladder. (PubMed, Pharmacol Res) - "Similarly, dovitinib, AZD4547, CH5183284, infigratinib, lenvatinib, LY2874455, and lucitanib are type I½ inhibitors...Ponatinib binds to FGFR4 in a DFG-D conformation and is classified as a type II inhibitor. Futibatinib, roblitinib, H3B-6527, fisogatinib, and PRN1371 bind covalently to their FGFR target and are classified as type VI inhibitors. Nintedanib, pazopanib, pemigatinib, rogaratinib, and PRN1371 are FGFR inhibitors lacking drug-enzyme crystal structures...The development of FGFR inhibitors has lagged behind those of other receptor protein-tyrosine kinases. However, the FDA approval of erdafitinib for the treatment of urinary bladder cancers may stimulate additional work targeting the many other FGFR-driven neoplasms."

Journal • Review • CSF1R • FGF23 • FGFR1 • FGFR4 • FLT1 • FLT3

FGF19 promotes esophageal squamous cell carcinoma progression by inhibiting autophagy (ESMO 2019) - "The effect of proliferation inhibition of LY2874455, which is inhibitor of fibroblast growth factor receptors (FGFR), was assessed in ESCC patient-derived cell (PDC) and xenograft (PDX) models... Our findings reveal that FGF19 amplification inhibits autophagic activity by increasing the phosphorylation level of ERK, which may play an essential role in the pathogenesis of ESCC. Using FGFR inhibitor may represent an effective strategy to suppress FGF19 amplificated ESCC development and progression. Legal entity responsible for the study: The authors."

Fibroblast Growth Factor Receptor Inhibition induces loss of matrix MCL1 and necrosis in Cholangiocarcinoma. (PubMed, J Hepatol) - "In conclusion, FGFR inhibition induces loss of matrix MCL1 resulting in cell necrosis. These observations support a heretofore unidentified, alternative MCL1 survival function, namely prevention of cell necrosis, and have implications for treatment of human CCA. Lay summary Herein, we report that therapeutic inhibition of a cell receptor expressed by bile duct cancer cells results in loss of a critical survival protein termed MCL1. Cellular depletion of MCL1 results in cell death of the cancer cells by a process characterized by cell rupture. Cell death by this process can stimulate the immune system and has implications for combination therapy employing receptor inhibition with immunotherapy."

IO Biomarker • Journal

Preclinical Evaluation of the Pan-FGFR Inhibitor LY2874455 in FRS2-Amplified Liposarcoma. (PubMed, Cells) - "The only FGF expressed by unstimulated non-responding cells was the intracellular ligand FGF11, whereas the responding cell lines expressed extracellular ligand FGF2. Our study supports LY2874455 as a better therapy than NVP-BGJ398 for FRS2-amplified liposarcoma, and a clinical trial is warranted."

Journal • Preclinical