Paralog-Specific Kinase Inhibition of FGFR4: Adding to the Arsenal of Anti-FGFR Agents

Abstract

Summary:In this issue of Cancer Discovery , Hagel and colleagues report the design and the in vitro and in vivo activity of a novel, irreversible, paralog-specifi c kinase inhibitor of FGFR4, BLU9931. This compound binds covalently to a cysteine residue in the hinge region of FGFR4 but not in FGFR1-3. BLU9931 induces tumor shrinkage in hepatocellular carcinoma models that express a functioning ligand/receptor complex consisting of FGF19/ FGFR4/KLB and adds to a growing list of anti-FGFR4 agents. Cancer Discov; 5(4); ©2015 AACR . Hagel et al., p. 424 (2). See related article byAlongside the identifi cation of cancers driven by FGFR activation, the past few years have delivered multiple second-and third-generation anti-FGFR agents. These include inhibitors with greater selectivity (e.g., AZD4547 and NVP-BGJ398), irreversible FGFR kinase inhibitors (FIIN-1, FIIN-2), mAbs specifi c to each family member (FGFR1-4), as well as allosteric inhibitors targeting the extracellular domain that inhibit receptor internalization (SSR128129E). With respect to the competitive kinase inhibitors, the search for greater FGFR selectivity was driven, to some extent, by the desire to reduce toxicity associated with VEGFR2 inhibition. However, the selection against VEGFR2 was accompanied by a loss of selectivity against FGFR4. As a result, almost all the competitive FGFR kinase inhibitors currently in phase I/II trials (AZD4547, NVP-BGJ398, JNJ-42756493, BAY1163877, Debio 1347, and LY2874455) show at least a 4-fold greater selectivity toward FGFR1-3 over FGFR4 ( 1 ).Hagel and colleagues ( 2 ) report the design and the activity of an FGFR4-specifi c inhibitor, BLU9931, in several models of hepatocellular carcinoma (HCC). This group utilized structure-based drug design to create a compound that binds covalently to Cys552 in the hinge region of FGFR4. This cysteine is unique to FGFR4, as FGFR1-3 possess a bulky tyrosine residue that clashes with BLU9931. As a result of modifying Cys552, BLU9931 is a potent and selective FGFR4 inhibitor (IC 50 = 3 nmol/L) with only weak activity against FGFR1-3 (IC 50 values range from ∼150 to 600 nmol/L). Furthermore, BLU9931 was unable to inhibit the six other kinases that also have a cysteine at the corresponding position within the hinge region.The group at Blueprint Medicines shows that BLU9931 inhibits FGFR4 and blocks phosphorylation of its substrates FRS2α, MAPK, and AKT at 10 to 30 nmol/L in the MDA-MB-453 breast cancer cell line carrying an activating Y367C mutation in FGFR4 , but not in DMS-11 lung cancer cells carrying amplifi cation of FGFR1 . With regard to HCC, they confi rmed previous reports with pan-FGFR inhibitors showing only cells expressing a fully functional receptor complex comprised of FGFR4, its coreceptor Klotho-β (KLB), and FGF19 respond to BLU9931 ( 3 ). Of the 11 HCC cell lines they tested, 4 cell lines expressed all three components, and 3 of these, all with FGF19 amplifi cation, were sensitive to BLU9931. The authors report that twice-daily 30-mg/kg doses led to tumor shrink...

H3B-6527 Is a Potent and Selective Inhibitor of FGFR4 in FGF19-Driven Hepatocellular Carcinoma

“…In this study, we have shown that inhibiting FGFR4 using a selective small molecule may provide therapeutic benefit to a subset of HCC patients with FGF19 overexpression. Although pan-FGFR inhibitors are undergoing clinical evaluation for a variety of indications, they are likely unsuitable for FGF19-driven HCC due to their low potency against FGFR4 (11). We exploited the unique hinge cysteine in the FGFR4 kinase domain to design a covalent inhibitor, H3B-6527, that specifically inhibits FGFR4 and largely spares other FGFRs.…”

“…These data suggest targeting FGFR4 would have therapeutic benefit in HCC with altered FGF19 signaling. While a number of pan-FGFR inhibitors are being clinically evaluated in a variety of indications, they display poor potency against FGFR4 potentially limiting their application to FGF19-driven HCC (11). Furthermore, pan-FGFR inhibitors with FGFR4 potency would likely be limited by their on-target FGFR1-3-mediated dose-limiting toxicities (hyperphosphatemia and soft-tissue mineralization), suggesting a need to improve FGFR4 selectivity (11).…”

“…While a number of pan-FGFR inhibitors are being clinically evaluated in a variety of indications, they display poor potency against FGFR4 potentially limiting their application to FGF19-driven HCC (11). Furthermore, pan-FGFR inhibitors with FGFR4 potency would likely be limited by their on-target FGFR1-3-mediated dose-limiting toxicities (hyperphosphatemia and soft-tissue mineralization), suggesting a need to improve FGFR4 selectivity (11). Emerging studies show that selective inhibition of FGFR4 by antibody and small-molecule approaches are being pursued given the strong link between FGF19, FGFR4, and oncogenesis in HCC (9,12).…”

FGFR4 Is a Potential Predictive Biomarker in Oral and Oropharyngeal Squamous Cell Carcinoma

“…Differences in affinity of FGFR inhibitors for FGFR family members has been explored by structural and biophysical comparison and the crystal structure of the FGFR4 kinase domain has recently been revealed [34]. The first selective small molecule inhibitors aimed at FGFR4 have just been developed [35,36]. …”

Inhibitors of the Fibroblast Growth Factor Receptor

“…It has been widely postulated that the ability to selectivity inhibit a single isoform of FGFR may result in compounds with improved therapeutic margins. In particular, there is evidence that inhibition of FGFR1 is associated with mineralization in preclinical models and may cause doselimiting effects in the clinic [44].…”