We describe the discovery and the structure-activity relationship of a new series of quinoline derivatives acting as selective and highly potent noncompetitive mGlu1 antagonists. We first identified cis-10 as a fairly potent mGlu1 antagonist (IC(50) = 20 nM) in a cell-based signal transduction assay on the rat mGlu1 receptor expressed in CHO-K1 cells, and then we were able to design and synthesize highly potent compounds on both rat and human mGlu1 receptors as exemplified by compound cis-64a, which has an antagonist potency of 0.5 nM for the human mGlu1 receptor. We briefly present and discuss the in vitro metabolic stability of the compounds in human liver microsomes. We finally report the pharmacokinetic properties of our lead compound cis-64a.
A novel Type II kinase inhibitor chemotype has been identified for maternal embryonic leucine zipper kinase (MELK) using structure-based ligand design. The strategy involved structural characterization of an induced DFG-out pocket by protein−ligand X-ray crystallography and incorporation of a slender linkage capable of bypassing a large gate-keeper residue, thus enabling design of molecules accessing both hinge and induced pocket regions. Optimization of an initial hit led to the identification of a low-nanomolar, cell-penetrant Type II inhibitor suitable for use as a chemical probe for MELK. KEYWORDS:Maternal embryonic leucine zipper kinase, fragment-based drug design, structure-based optimization M aternal embryonic leucine zipper kinase (MELK) has been suggested as a promising target for cancer treatment 1 with reports of increased MELK expression in multiple cancer types. 2−7 One challenge in assessing the biological role of MELK has been the lack of well-characterized selective inhibitors. For example, the MELK inhibitor OTSSP167 has shown promising activity in a number of phenotypic assays but no selectivity data is disclosed. 8 However, we recently reported the use of fragment-based drug design 9 (FBDD) to obtain MELK-T1 1, a selective chemical probe for MELK inhibition. 10 In this approach, a fragment binding to the hinge backbone was optimized by structure-guided design into a selective low nanomolar inhibitor. Protein−ligand X-ray crystallography of the MELK complex with 1 showed that the conserved Asp-Phe-Gly motif in the kinase activation loop adopted the so-called DFG-in conformation; MELK-T1 thus exemplifies a Type I inhibitor, albeit with an atypical trans-amide hinge binding motif. We were also interested in accessing Type II inhibitors, typified by a DFG-out conformation of the activation loop.A number of design approaches to Type II inhibitors have been reported, 11 but for MELK, several challenges had to be overcome. Existing Type II chemotypes tend toward high molecular weight and lipophilicity because the molecules span a large distance between the hinge region and a back pocket beyond the gate-keeper residue characteristic of DFG-out structures. Our aim was to generate inhibitors with good ligand efficiency (LE), 12 suitable for use as chemical probes in cellbased assays and as starting points for efficient optimization into drug candidates. A second challenge was the large size of the gate-keeper (GK) residue for MELK, namely, Leu86. For a putative molecule binding to both hinge and back pocket, a large GK provides a steric barrier for any linkage, so affording a significant design challenge. Typical Type II inhibitors present an amide or urea linker in the region between the hinge and back pocket; accommodation of such groups is more challenging with a large GK. However, we were encouraged that Type II structures are precedented for c-Met, where the GK is also leucine. 13 Another potential difficulty was obtaining high quality structural information on a DFG-out form of MELK. T...
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
Chromosomal rearrangements resulting in oncogenic fusion proteins containing the ROS1 receptor tyrosine kinase have been described in subsets of a variety of human malignancies including non-small-cell lung cancer (NSCLC), cholangiocarcinoma, and glioblastoma multiforme. Promising clinical responses have been observed in patients bearing tumors with ROS1 fusions treated with Xalkori, an ALK/MET kinase inhibitor that also inhibits Ros1. However, resistance has been observed and a ROS1 kinase domain mutation, G2032R, was identified in a ROS1 fusion positive NSCLC patient who developed resistance to Xalkori treatment. Clinical experience with other receptor tyrosine kinase inhibitors suggests that additional resistance mutations are likely to arise, highlighting the need for therapeutic agents that can overcome this type of resistance. We identified a novel chemical series of potent and selective Ros1 inhibitors with a unique DFG-out binding mode. The structure of human Ros1 in a complex with a ligand from this chemical class was confirmed by X-ray crystallography. Here we describe the structure-activity relationships and synthesis route for this chemical series. A representative compound from this series inhibited isolated recombinant Ros1 kinase activity with an IC50 of approximately 30 nM. This compound inhibited less than 6% of kinases in a panel of 400 at 1 μM concentration. Growth of Ba/F3 cells engineered to express Ros1 autophosphorylation in HCC78 NSCLC cells that harbor a SLC34A2-ROS1 fusion were inhibited at similar concentrations as the isolated protein. This activity translated into potent Ba/F3-Ros1 tumor growth inhibition in mice. This compound was also active on Ba/F3 cells containing Ros1 with a mutation in the gatekeeper residue, L2026M, in cell growth assays in vitro and tumor growth in vivo. Furthermore, this unique binding mode provides scope for activity on additional Ros1 mutations that confer resistance to Xalkori, such as the clinically relevant G2032R mutation. The results shown here describe a novel chemical series with a unique binding mode that has potential for activity in Ros1 driven tumors with mutations that confer resistance to Xalkori. Citation Format: Laurence Mevellec, Berthold Wroblowski, Ron Gilissen, Sophie Descamps, Elisabeth Pasquier, Christophe Adelinet, Marine Bourgeois, Guillaume Mercey, Matthieu Jeanty, Thierry Jousseaume, Aurélie Luguern, Javier Astray Gandara, Said Akzinnay, Etienne Daras, Inge Boeckx, Nele Van Slycken, Mariette Bekkers, Jeroen Van De Ven, Tinne Verhulst, Lieven Meerpoel, Jorge Vialard. Discovery of potent and selective Ros1 inhibitors with a unique DFG-out binding mode. [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 4745. doi:10.1158/1538-7445.AM2014-4745
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.