Discovery of a σ1 receptor antagonist by combination of unbiased cell painting and thermal proteome profiling

Banks, 2019, Small molecules as central nervous system therapeutics: old challenges, new directions, and a philosophic divide, Future Med. Chem., 11, 489, 10.4155/fmc-2018-0436 Beart, 1989, Regulation of σ-receptors: high- and low-affinity agonist states, GTP shifts, and up-regulation by rimcazole and 1,3-di(2-tolyl)guanidine, J. Neurochem., 53, 779, 10.1111/j.1471-4159.1989.tb11773.x Bray, 2016, Cell Painting, a high-content image-based assay for morphological profiling using multiplexed fluorescent dyes, Nat. Protoc., 11, 1757, 10.1038/nprot.2016.105 Brent, 1996, Kappa opioid receptor agonists inhibit sigma-1 (σ1) receptor binding in guinea-pig brain, liver and spleen: autoradiographical evidence, Brain Res., 725, 155, 10.1016/0006-8993(96)00170-9 Carpenter, 2006, CellProfiler: image analysis software for identifying and quantifying cell phenotypes, Genome Biol., 7, 1, 10.1186/gb-2006-7-10-r100 Cheng, 1973, Relationship between the inhibition constant (KI) and the concentration of inhibitor which causes 50 per cent inhibition (I50) of an enzymatic reaction, Biochem. Pharmacol., 22, 3099, 10.1016/0006-2952(73)90196-2 Christoforow, 2019, Design, synthesis, and phenotypic profiling of pyrano-furo-pyridone pseudo natural products, Angew. Chem. Int. Ed., 58, 14715, 10.1002/anie.201907853 Cobos, 2005, Phenytoin differentially modulates the affinity of agonist and antagonist ligands for σ1 receptors of guinea pig brain, Synapse, 55, 192, 10.1002/syn.20103 Cox, 2008, MaxQuant enables high peptide identification rates, individualized p.p.b.-range mass accuracies and proteome-wide protein quantification, Nat. Biotechnol., 26, 1367, 10.1038/nbt.1511 DeHaven-Hudkins, 1992, Characterization of the binding of [3H](+)-pentazocine to σ recognition sites in guinea pig brain, Eur. J. Pharmacol. Mol. Pharmacol., 227, 371, 10.1016/0922-4106(92)90153-M Eggert, 2013, The why and how of phenotypic small-molecule screens, Nat. Chem. Biol., 9, 206, 10.1038/nchembio.1206 Entrena, 2009, Antagonism by haloperidol and its metabolites of mechanical hypersensitivity induced by intraplantar capsaicin in mice: role of sigma-1 receptors, Psychopharmacology, 205, 21, 10.1007/s00213-009-1513-8 Entrena, 2009, Sigma-1 receptors are essential for capsaicin-induced mechanical hypersensitivity: studies with selective sigma-1 ligands and sigma-1 knockout mice, PAIN, 143, 252, 10.1016/j.pain.2009.03.011 Foley, 2020, Phenotyping reveals targets of a pseudo-natural-product autophagy inhibitor, Angew. Chem. Int. Ed., 59, 12470, 10.1002/anie.202000364 Glennon, 2005, Pharmacophore identification for sigma-1 (σ1) receptor binding: application of the "deconstruction-reconstruction-elaboration" approach, Mini Rev. Med. Chem., 5, 927, 10.2174/138955705774329519 Gustafsdottir, 2013, Multiplex cytological profiling assay to measure diverse cellular states, PLoS One, 8, e80999, 10.1371/journal.pone.0080999 Hayashi, 2004, Sigma-1 receptor ligands: potential in the treatment of neuropsychiatric disorders, CNS drugs, 18, 269, 10.2165/00023210-200418050-00001 Hudkins, 1991, M1 muscarinic antagonists interact with σ recognition sites, Life Sci., 49, 1229, 10.1016/0024-3205(91)90135-X Ishima, 2014, Interaction of new antidepressants with sigma-1 receptor chaperones and their potentiation of neurite outgrowth in PC12 cells, Eur. J. Pharmacol., 727, 167, 10.1016/j.ejphar.2014.01.064 Kedjouar, 1999, Structural similitudes between cytotoxic antiestrogen-binding site (AEBS) ligands and cytotoxic sigma receptor ligands. Evidence for a relationship between cytotoxicity and affinity for AEBS or sigma-2 receptor but not for sigma-1 receptor, Biochem. Pharmacol., 58, 1927, 10.1016/S0006-2952(99)00285-3 Laraia, 2020, Image-based morphological profiling identifies a lysosomotropic, iron-sequestering autophagy inhibitor, Angew. Chem. Int. Ed., 59, 5721, 10.1002/anie.201913712 Lee, 2008, An unambiguous assay for the cloned human sigma1 receptor reveals high affinity interactions with dopamine D4 receptor selective compounds and a distinct structure–affinity relationship for butyrophenones, Eur. J. Pharmacol., 578, 123, 10.1016/j.ejphar.2007.09.020 Mach, 1995, Ibogaine possesses a selective affinity for σ2 receptors, Life Sci., 57, PL57, 10.1016/0024-3205(95)00301-L Maisonial-Besset, 2014, Automation of the radiosynthesis and purification procedures for [18F]fluspidine preparation, a new radiotracer for clinical investigations in PET imaging of σ1 receptors in brain, Appl. Radiat. Isot., 84, 1, 10.1016/j.apradiso.2013.10.015 Marceau, 2012, Cation trapping by cellular acidic compartments: beyond the concept of lysosomotropic drugs, Toxicol. Appl. Pharmacol., 259, 1, 10.1016/j.taap.2011.12.004 Martinez Molina, 2016, The cellular thermal shift assay: a novel biophysical assay for in situ drug target engagement and mechanistic biomarker studies, Annu. Rev. Pharmacol. Toxicol., 56, 141, 10.1146/annurev-pharmtox-010715-103715 Mateus, 2017, Thermal proteome profiling: unbiased assessment of protein state through heat-induced stability changes, Proteome Sci., 15, 13, 10.1186/s12953-017-0122-4 Matsumoto, 2001, Conformationally restricted analogs of BD1008 and an antisense oligodeoxynucleotide targeting σ1 receptors produce anti-cocaine effects in mice, Eur. J. Pharmacol., 419, 163, 10.1016/S0014-2999(01)00968-2 McLarnon, 1994, The actions of L-687,384, a sigma receptor ligand, on NMDA-induced currents in cultured rat hippocampal pyramidal neurons, Neurosci. Lett., 174, 181, 10.1016/0304-3940(94)90016-7 Merlos, 2017, Sigma-1 receptor and pain, 131 Narita, 1996, Interactions of selective serotonin reuptake inhibitors with subtypes of σ receptors in rat brain, Eur. J. Pharmacol., 307, 117, 10.1016/0014-2999(96)00254-3 Pahl, 2019, The Cell Painting assay as a screening tool for the discovery of bioactivities in new chemical matter, 115 Perregaard, 1995, σ Ligands with subnanomolar affinity and preference for the σ2 binding site. 1. 3-(ω-aminoalkyl)-1H-indoles, J. Med. Chem., 38, 1998, 10.1021/jm00011a019 Pontén, 2008, The human protein atlas - a tool for pathology, J. Pathol., 216, 387, 10.1002/path.2440 Rao, 1990, Neurochemical characterization of dopaminergic effects of opipramol, a potent sigma receptor ligand, in vivo, Neuropharmacology, 29, 1191, 10.1016/0028-3908(90)90044-R Reckzeh, 2019, Target engagement of small molecules: thermal profiling approaches on different levels, 73 Savitski, 2014, Tracking cancer drugs in living cells by thermal profiling of the proteome, Science, 346, 1255784, 10.1126/science.1255784 Schepmann, 2020, Pharmacological characterization of high-affinity σ1 receptor ligands with spirocyclic thienopyran and thienofuran scaffold, J. Pharm. Pharmacol., 72, 236, 10.1111/jphp.13196 Schindelin, 2012, Fiji: an open-source platform for biological-image analysis, Nat. Methods, 9, 676, 10.1038/nmeth.2019 Schneidewind, 2020, Morphological profiling identifies a common mode of action for small molecules with different targets, Chembiochem, 21, 3197, 10.1002/cbic.202000381 Du Sert, 2020, Reporting animal research: explanation and elaboration for the ARRIVE guidelines 2.0, PLoS Biol., 18, e3000411, 10.1371/journal.pbio.3000411 Tam, 1983, Naloxone-inaccessible sigma receptor in rat central nervous system, Proc. Natl. Acad. Sci. U S A, 80, 6703, 10.1073/pnas.80.21.6703 Tam, 1984, Sigma opiates and certain antipsychotic drugs mutually inhibit (+)-3H SKF 10,047 and 3Hhaloperidol binding in guinea pig brain membranes, Proc. Natl. Acad. Sci. U S A, 81, 5618, 10.1073/pnas.81.17.5618 Tesei, 2018, Sigma receptors as endoplasmic reticulum stress “gatekeepers” and their modulators as emerging new weapons in the fight against cancer, Front. Pharmacol., 9, 711, 10.3389/fphar.2018.00711 Wilkinson, 2020, Combining experimental strategies for successful target deconvolution, Drug Discov. Today, 25, 1998, 10.1016/j.drudis.2020.09.016 Woehrmann, 2013, Large-scale cytological profiling for functional analysis of bioactive compounds, Mol. Biosyst., 9, 2604, 10.1039/c3mb70245f Ziegler, 2013, Target identification for small bioactive molecules: finding the needle in the haystack, Angew. Chem. Int. Ed, 52, 2744, 10.1002/anie.201208749 Zimmermann, 2019, A scaffold-diversity synthesis of biologically intriguing cyclic sulfonamides, Chemistry, 25, 15498, 10.1002/chem.201904175