Olivier Querolle

Access to Silylated Pyrazole Derivatives by Palladium-Catalyzed C-H Activation of a TMS group.

A simple and efficient approach to new silylated heterocycles of potential interest in medicinal chemistry is presented. A set of bromophenyl trimethylsilyl pyrazole intermediates can be transformed by direct organometallic routes into two families of regioisomeric iodoaryl substrates; using either arylzinc or aryllithium chemistry, the TMS group remains on the pyrazole ring or translocates to the aryl moiety. These two families can then be efficiently transformed into benzo silino pyrazoles thanks to a single-step cyclization relying on the Pd-catalyzed activation of a non-activated C(sp(3) )-H bond alpha to a silicon atom. The experimental conditions used, which are fully compatible with the pyrazole ring, suggest that this reaction evolves through a concerted metalation-deprotonation (CMD) mechanism.

Anionic Access to Silylated and Germylated Binuclear Heterocycles

A simple access to silylated and germylated binuclear heterocycles, based on an original anionic rearrangement, is described. A set of electron-rich and electron-poor silylated aromatic and heteroaromatic substrates were tested to understand the mechanism and the factors controlling this rearrangement, in particular its regioselectivity. This parameter was shown to follow the rules proposed before from a few examples. Then, the effect of the substituents borne by the silicon itself, in particular the selectivity of the ligand transfer, was studied. Additionally, this chemistry was extended to germylated substrates. A hypervalent germanium species, comparable to the putative intermediate proposed with silicon, seems to be involved. However, a pathway implicating the elimination of LiCH2Cl was observed for the first time with this element, leading to unexpected products of the benzo-oxa (or benzo-aza) germol-type.

Intramolecular sila-Matteson rearrangement: a general access to silylated heterocycles.

A series of new silylated heterocycles has been efficiently prepared using an intramolecular silicon version of the Matteson rearrangement, providing two isomers of binuclear heterocycles. This method applies to a large variety of substrates, a direct relationship between the Hammett constants of the aromatic substituents and the isomer ratio being observed. Complementary experiments suggest that a common pentaorganosilicate species is involved.

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

Proceedings: AACR Annual Meeting 2014; April 5-9, 2014; San Diego, CA 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

Abstract 4199: Inhibition of NF-kB inducing kinase (NIK) selectively abrogates NIK and TRAF3 mutant multiple myeloma tumor growth

Enhanced NF-kB signaling is a hallmark of aggressive lymphoid malignancies, including multiple myeloma (MM), mantle cell lymphoma (MCL), and diffuse large B-cell lymphoma (DLBCL). Non-canonical NF-kB signaling involves NIK-dependent activation of IKKα, which triggers nuclear accumulation of p52/RelB heterodimers. NIK is a highly unstable protein and degradation is mediated by a ubiquitin ligase complex consisting of TRAF2, TRAF3 and c-IAP1/2 (encoded by BIRC2/3). In a subset of MM, NIK is stabilized by mutations in NIK, TRAF2/3 or BIRC2/3 (Annunziata et al./Keats et al., Canc. Cell 2007). Similar activating mutations in the non-canonical NF-kB signaling pathway were recently found in ibrutinib-refractory MCL cell lines (Rahal et al., Nat. Med. 2014), and in DLBCL (Zhang et al., Cell Rep. 2015). In many other cases of B-cell malignancies, NIK is stabilized by high level expression of the upstream TNF receptors (BAFFR, CD40, LTβR) or high abundance of their ligands in the bone marrow or the lymph nodes. To date, bioavailable NIK inhibitors have not been reported, and it has remained unclear whether NIK inhibitors are effective and tolerated in mouse models of B-cell malignancies associated with activation of NIK. Here, we report for the first time on a potent orally bioavailable NIK kinase inhibitor, TRC694. TRC694 selectively inhibits NIK enzymatic activity, translating into inhibition of phospho-IKKα in NIK and in TRAF3 mutant cell lines with single digit nM IC50. TRC694 prevents nuclear accumulation of p52/RelB (but not canonical NF-kB) and represses the associated NF-kB gene program selectively in MM cell lines with genetic activation of the non-canonical NF-kB pathway. Proliferation of NIK translocated, TRAF3 or BIRC3 mutant MM cell lines is inhibited by low nM concentrations of TRC694, whereas MM cell lines which lack genetic activation of non-canonical NF-kB are much less sensitive to TRC694. Consistently, elevated expression of a previously described 11-gene NFkB signature in MM (Annunziata et al., Canc. Cell 2007) is predictive of sensitivity to TRC694 in a 21-MM cell line panel. A single, oral dose of 10 to 40 mg/kg of TRC694 to mice bearing a NIK-translocated MM tumor (JJN-3), was sufficient to inhibit phospho-IKKα and repress P52-mediated transcription of NFkB regulated genes in the tumors. Consistently, once-daily, oral dosing of TRC694 to mice bearing subcutaneous NIK translocated (JJN-3) or TRAF3 (RPMI-8226, MM.1S) mutant MM tumors, completely inhibits growth of these tumors at doses of 10 to 40 mg/kg, with no signs of toxicities. In conclusion, TRC694 is a first-in-class orally bioavailable NIK kinase inhibitor, and provides the first opportunity to test the clinical relevance of non-canonical NF-kB inhibition in aggressive lymphoid malignancies. Citation Format: Matthias Versele, Lut Janssen, Tamara Geerts, Wim Floren, Boudewijn Janssens, Hillary Millar, Edgar Jacoby, Gerhard Gross, Yannick Ligny, Yvan Simonnet, Nathalie Amblard, Olivier Querolle, Imre Csoka, Virginie Poncelet, Virginie Tronel, Sophie Nocquet-Thibault, Lieven Meerpoel, James Edwards, Marc Salvati, Sriram Balasubramanian, Laurie Lenox, Charles Theuer, Ricardo Attar, Ian Stansfield. Inhibition of NF-kB inducing kinase (NIK) selectively abrogates NIK and TRAF3 mutant multiple myeloma tumor growth [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4199. doi:10.1158/1538-7445.AM2017-4199

Abstract 3640: Discovery of quinazolinones as fibroblast growth factor receptor (FGFR1-4) kinase inhibitors

Recent data obtained in several tumor types have identified Fibroblast Growth Factor signaling as a key factor in the molecular pathology of a number of cancers1. This has stimulated the development of a number of agents that block this pathway, including FGFR kinase inhibitors with diverse inhibition and pharmacological profiles that are currently being evaluated in clinical studies. We recently reported that a quinoxaline moiety can efficiently bind the hinge region of FGFR kinase catalytic sites. In continuation of our efforts to discover additional FGFR1-4 inhibitors, we have identified a quinazolinone scaffold as a novel FGFR kinase hinge binder. Initial hits were optimized into compounds displaying nanomolar affinity for FGFR1-4, potent activity in FGFR driven cells and efficacy in a Ba/F3-FGFR3 xenograft model. This report represents the first disclosure of the structure-activity relationships as well as the chemical synthesis pathways of these novel quinazolinone-based FGFR1-4 inhibitors. Turner N. and Grose R. Nature Reviews-Cancer 2010, 10, 116-129 Citation Format: Olivier Querolle, Patrick Angibaud, Helene Colombel, Virginie Caron, Isabelle Pilatte, Virginie Poncelet, Norbert Esser, Ron Gilissen, Peter King, Lieven Meerpoel, Tinne Verhulst, Berthold Wroblowski, Jorge Vialard, Chris W. Murray, David C. Rees, Anita Reningovolo, Gordon Saxty. Discovery of quinazolinones as fibroblast growth factor receptor (FGFR1-4) kinase inhibitors. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3640. doi:10.1158/1538-7445.AM2015-3640