Abstract 4748: Discovery of JNJ-42756493, a potent fibroblast growth factor receptor (FGFR) inhibitor using a fragment based approach

Abstract

Fibroblast growth factors (FGFs) and their receptors (FGFR1 through 4) regulate a variety of key cellular processes, including proliferation, migration, survival, and differentiationa. Aberrant activation of FGF/FGFR is strongly implicated in oncogenic signalling in many tumor types. This has stimulated the development of a number of FGFR inhibitors, with diverse kinase inhibition and pharmacological profiles that are currently being evaluated in clinical studies. We conducted a fragment screening campaign and this resulted in identification of a 6-aminoquinoxalinyl fragment with a binding affinity in the micromolar range. Structure-guided medicinal chemistry led to the identification of a novel quinoxaline-based chemical series with nanomolar affinity for FGFR1, 2, 3, and 4, activity in cells, and selectivity with respect to VEGFR-2. Further optimisation resulted in the generation of JNJ-42756493, a compound with favourable drug-like properties that demonstrated strong anti-tumoral activity in a FGFR2-dependent SNU-16 human gastric carcinoma xenograft model. This report represents the first disclosure of the structure-activity relationships as well as the chemical synthesis pathway of the JNJ-42756493 series and illustrates how a fragment-based drug discovery approach has been efficiently used to discover FGFR1-4 inhibitors with nanomolar affinity. aTurner, N. and Grose, R. Nat. Rev. Cancer, 2010, 10, 116-129. Citation Format: Patrick R. Angibaud, Laurence Mevellec, Gordon Saxty, Christophe Adelinet, Rhalid Akkari, Valerio Berdini, Pascal Bonnet, Marine Bourgeois, Xavier Bourdrez, Anne Cleasby, Helene Colombel, Imre Csoka, Werner Embrechts, Eddy Freyne, Ronaldus Gilissen, Eleonora Jovcheva, Peter King, Jean Lacrampe, Delphine Lardeau, Yannick Ligny, Steve Mcclue, Lieven Meerpoel, David R. Newell, Martin Page, Alexandra Papanikos, Elisabeth Pasquier, Isabelle Pilatte, Virginie Poncelet, Olivier Querolle, David C. Rees, Sharna Rich, Bruno Roux, Elodie Sement, Yvan Simonnet, Matthew Squires, Virginie Tronel, Tinne Verhulst, Jorge Vialard, Marc Willems, Steven J. Woodhead, Berthold Wroblowski, Christopher W. Murray, Timothy Perera. Discovery of JNJ-42756493, a potent fibroblast growth factor receptor (FGFR) inhibitor using a fragment based approach. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4748. doi:10.1158/1538-7445.AM2014-4748

Targeting FGFR1 to suppress leukemogenesis in syndromic and de novo AML in murine models

“…Among these, inhibitors AZD4547, BGJ398 and JNJ42756493, were selected because they have been shown to effectively inhibit FGFR1 kinase in biochemical assays [19–22]. However, since each inhibitor has been investigated in isolation, in different model systems, it has not been possible to determine the relative efficacy and specificity of these drugs in inhibiting FGFR1 activity and related phenotypes.…”

“…Recently, several additional, more specific pan-FGFR inhibitors have been developed, such as AZD4547 [19], BGJ398 [20, 21], JNJ42756493 [22] and LY2874455 [23], in addition to multi-target inhibitors such as ponatinib (also known as AP24534) [24], TKI258 [25] and E3810 [26]. Ponatinib (Iclusig ® ) is an FDA approved drug for the treatment of chronic myeloid leukemia (CML) and Philadelphia chromosome–positive acute lymphoblastic leukemia (ALL).…”

Mutation in the FGFR1 tyrosine kinase domain or inactivation of PTEN is associated with acquired resistance to FGFR inhibitors in FGFR1‐driven leukemia/lymphomas

“…Ponatinib, which was originally developed to target the BCR‐ABL, T315I mutation, was shown to also inhibit FGFR1 at low concentrations and is particularly effective against FGFR1 driven neoplasms but also inhibits other kinases such as KIT and FLT3. More recently, however, more specific FGFR inhibitors such as ADZ4547, JNJ42756493 and BGJ398 have been developed. We have evaluated the relative efficiency of these different FGFR1 inhibitors in suppressing growth of leukemic cells lines expressing chimeric FGFR1 kinases and demonstrated that they are highly effective in suppressing in vitro growth at nanomolar concentrations, and have demonstrated the effectiveness of BGJ398 against SCLL syndromic and de novo FGFR1 overexpressing AML in vivo , paving the way for clinical trials using FGFR1 inhibitors in subtypes of AML overexpressing FGFR1.…”

Small Molecule Kinase Inhibitors for the Treatment of Brain Cancer

“…As many of the FGFR inhibitors are nonselective, with many inhibiting VEGFR and PDGFR (discussed above), the focus of this section is limited to selective FGFR inhibitors that have entered clinical development (Table ). Those inhibitors include AZD4547 ( 40 ), infigratinib ( 41 ), erdafitinib ( 42 ), CH5183284 ( 43 ), and ARQ 087 (structure not available). Of these, infigratinib has advanced to clinical studies in patients with GBM .…”