Discovery of 1,6-Naphthyridin-2(1H)-one Derivatives as Novel, Potent, and Selective FGFR4 Inhibitors for the Treatment of Hepatocellular Carcinoma

Abstract

Fibroblast growth factor receptor 4 (FGFR4) has been identified as a potential target due to its transmission of the FGF19 signaling pathway, which is critical to hepatocellular carcinoma (HCC). Therefore, focusing on the specific Cys552 of FGFR4 subtype, we designed and synthesized a novel family of 1,6-naphthyridin-2­(1H)-one derivatives as potent and highly selective FGFR4 inhibitors. Through detailed structural optimizations, the representative compound A34 exhibited improved FGFR4 inhibitory capability and selectivity and excellent anti-proliferative activities against FGFR4-dependent HCC cell lines. Additionally, A34 demonstrated remarkable antitumor efficacy in a Hep-3B HCC xenograft model, with favorable pharmacokinetic properties, and low risk of hERG toxicity. A34 also showed moderate inhibitory activities against the FGFR4 V550L mutant in vitro, which indicates that it has the potential as a novel anticancer agent for HCC.

Discovery of Novel Indazole Chemotypes as Isoform-Selective JNK3 Inhibitors for the Treatment of Parkinson’s Disease

“…Due to the expression of JNK3 in the heart, the effect of compound 25c on hERG (human Ether-a-go-go Related Gene) potassium channel currents was tested to evaluate its heart toxicity by a patch-clamp experiment, with terfenadine as a standard control (Figure B). As shown in Figure A, the IC 50 value of 25c against hERG exceeded 30 μM, indicating that 25c showed a relatively low risk of cardiotoxicity …”

“…As shown in Figure 7A, the IC 50 value of 25c against hERG exceeded 30 μM, indicating that 25c showed a relatively low risk of cardiotoxicity. 52 2.8. Pharmacokinetic Profiles and Blood−Brain Barrier Permeability of Compound 25c.…”

Design, Synthesis, and Biological Evaluation of 5-Formyl-pyrrolo[3,2-b]pyridine-3-carboxamides as New Selective, Potent, and Reversible-Covalent FGFR4 Inhibitors

“… Another FGFR4-selective irreversible inhibitor H3B-6527 ( 5 ), designed by incorporating an acrylamide moiety into the ortho-position of the aniline ring of the pan-FGFR inhibitor BGJ398 (infigratinib), is under clinical evaluation for the treatment of HCC (NCT02834780) . In addition, other reported selective FGFR4 inhibitors are in an early stage of development. − Recently, concerns about potentially undesirable side effects of irreversible inhibitors and a relatively rapid FGFR4 resynthesis rate in HCC cells (less than 2 h) have led Novartis to develop the reversible-covalent inhibitor FGF401 (roblitinib, 6 ). , Roblitinib has entered phase I/II clinical trial for the treatment of HCC and other solid tumors harboring abnormal FGFR4 signaling (NCT02325739). Unlike irreversible inhibitors, the aldehyde group of FGF401 forms an unstable hemi-thioacetal adduct with Cys552 of FGFR4 to achieve reversible-covalent target inhibition and prolonged residence time. , Despite the successful design of covalent inhibitors targeting Cys552 of FGFR4, no FGFR4-selective inhibitors have been approved by the FDA to date.…”

Discovery of 2-Amino-7-sulfonyl-7H-pyrrolo[2,3-d]pyrimidine Derivatives as Potent Reversible FGFR Inhibitors with Gatekeeper Mutation Tolerance: Design, Synthesis, and Biological Evaluation

“…However, the kinase domains of FGFR1–4 are highly conserved, while Cys552 in FGFR4 is a tyrosine in FGFR1–3 . The major difference in FGFR4 is that it is often covalently targeted by selective FGFR4 inhibitors. − The FGFR signaling pathway performs essential functions in physiological processes such as embryonic development, organ formation, cell proliferation, wound healing, and angiogenesis. , However, the aberrant FGFR signaling pathway is widely associated with cancer development. FGFR aberrations are found in 7.1% of 4853 tumor samples by next-generation sequencing (NGS) analysis, 66% of which are gene amplifications, more specifically, FGFR4 amplification in 33% of hepatocellular carcinoma (HCC), FGFR1 amplification in 20% of non-small cell lung carcinoma (NSCLC), and FGFR2 amplification in 5–10% of gastric cancer .…”

“…21 GK mutants of FGFR1−3, namely, FGFR1 V561M , FGFR2 V564F , and FGFR3 V555M , also induce acquired resistance in clinical studies of pemigatinib (2) and infigratinib (3). 18,26,27 FGFR inhibitors with similar back pocket structures and binding modes are also at risk of GK mutations, namely, futibatinib (5), 28 rogaratinib (6), 29 and derazantinib (7). 30 Although FGFR inhibitors demonstrate favorable clinical benefits, acquired resistance through GK mutations in FGFR is a major hurdle in the clinic and in the way of better exploiting FGFR as a validated target.…”