LY2874455

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.

We provide prospective, preliminary evidence that MET and FGFR are biologically active and safely targetable pathways in AML.

Our results pave the way for precision medicine approaches against FGFR4 V550L-driven RMS.

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.

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.

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, fisogatinib, 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.

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.

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.