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Discovery of novel Cyclophilin D inhibitors starting from three dimensional fragments with millimolar potencies.
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Grädler U, Schwarz D, Blaesse M, Leuthner B, Johnson TL, Bernard F, Jiang X, Marx A, Gilardone M, Lemoine H, Roche D, Jorand-Lebrun C
OpenAccess logo Bioorg Med Chem Lett 29 126717 (2019)
Related entries: 6r8l, 6r8o, 6r8w, 6r9s, 6r9u, 6ra1

Cited: 15 times
EuropePMC logo PMID: 31635932

Abstract

Fragment-based screening by SPR enabled the discovery of chemical diverse fragment hits with millimolar binding affinities to the peptidyl-prolyl isomerase Cyclophilin D (CypD). The CypD protein crystal structures of 6 fragment hits provided the basis for subsequent medicinal chemistry optimization by fragment merging and linking yielding three different chemical series with either urea, oxalyl or amide linkers connecting millimolar fragments in the S1' and S2 pockets. We successfully improved the in vitro CypD potencies in the biochemical FP and PPIase assays and in the biophysical SPR binding assay from millimolar towards the low micromolar and submicromolar range by >1000-fold for some fragment derivatives. The initial SAR together with the protein crystal structures of our novel CypD inhibitors provide a suitable basis for further hit-to-lead optimization.

Articles - 6r9x mentioned but not cited (2)

  1. Discovery of novel Cyclophilin D inhibitors starting from three dimensional fragments with millimolar potencies. Grädler U, Schwarz D, Blaesse M, Leuthner B, Johnson TL, Bernard F, Jiang X, Marx A, Gilardone M, Lemoine H, Roche D, Jorand-Lebrun C. Bioorg Med Chem Lett 29 126717 (2019)
  2. Tamoxifen Sensitizes Acute Lymphoblastic Leukemia Cells to Cannabidiol by Targeting Cyclophilin-D and Altering Mitochondrial Ca2+ Homeostasis. Olivas-Aguirre M, Torres-López L, Gómez-Sandoval Z, Villatoro-Gómez K, Pottosin I, Dobrovinskaya O. Int J Mol Sci 22 8688 (2021)


Reviews citing this publication (2)

  1. Concepts and Core Principles of Fragment-Based Drug Design. Kirsch P, Hartman AM, Hirsch AKH, Empting M. Molecules 24 E4309 (2019)
  2. Non-Immunosuppressive Cyclophilin Inhibitors. Schiene-Fischer C, Fischer G, Braun M. Angew Chem Int Ed Engl 61 e202201597 (2022)

Articles citing this publication (11)

  1. Combined Protein- and Ligand-Observed NMR Workflow to Screen Fragment Cocktails against Multiple Proteins: A Case Study Using Bromodomains. Johnson JA, Olson NM, Tooker MJ, Bur SK, Pomerantz WCK. Molecules 25 E3949 (2020)
  2. Discovery and molecular basis of subtype-selective cyclophilin inhibitors. Peterson AA, Rangwala AM, Thakur MK, Ward PS, Hung C, Outhwaite IR, Chan AI, Usanov DL, Mootha VK, Seeliger MA, Liu DR. Nat Chem Biol 18 1184-1195 (2022)
  3. Demonstration of the utility of DOS-derived fragment libraries for rapid hit derivatisation in a multidirectional fashion. Kidd SL, Fowler E, Reinhardt T, Compton T, Mateu N, Newman H, Bellini D, Talon R, McLoughlin J, Krojer T, Aimon A, Bradley A, Fairhead M, Brear P, Díaz-Sáez L, McAuley K, Sore HF, Madin A, O'Donovan DH, Huber KVM, Hyvönen M, von Delft F, Dowson CG, Spring DR. Chem Sci 11 10792-10801 (2020)
  4. Early Drug Discovery and Development of Novel Cancer Therapeutics Targeting DNA Polymerase Eta (POLH). Wilson DM, Duncton MAJ, Chang C, Lee Luo C, Georgiadis TM, Pellicena P, Deacon AM, Gao Y, Das D. Front Oncol 11 778925 (2021)
  5. Efficient and practical synthesis of monoalkyl oxalates under green conditions. Barsukova T, Sato T, Takumi H, Niwayama S. RSC Adv 12 25669-25674 (2022)
  6. Evaluating the use of absolute binding free energy in the fragment optimisation process. Alibay I, Magarkar A, Seeliger D, Biggin PC. Commun Chem 5 105 (2022)
  7. A New Drug Discovery Platform: Application to DNA Polymerase Eta and Apurinic/Apyrimidinic Endonuclease 1. Das D, Duncton MAJ, Georgiadis TM, Pellicena P, Clark J, Sobol RW, Georgiadis MM, King-Underwood J, Jobes DV, Chang C, Gao Y, Deacon AM, Wilson DM. Int J Mol Sci 24 16637 (2023)
  8. Exploration of piperidine 3D fragment chemical space: synthesis and 3D shape analysis of fragments derived from 20 regio- and diastereoisomers of methyl substituted pipecolinates. Jones SP, Firth JD, Wheldon MC, Atobe M, Hubbard RE, Blakemore DC, De Fusco C, Lucas SCC, Roughley SD, Vidler LR, Whatton MA, Woolford AJ, Wrigley GL, O'Brien P. RSC Med Chem 13 1614-1620 (2022)
  9. Extract2Chip-Bypassing Protein Purification in Drug Discovery Using Surface Plasmon Resonance. Paiva ACF, Lemos AR, Busse P, Martins MT, Silva DO, Freitas MC, Santos SP, Freire F, Barrey EJ, Manival X, Koetzner L, Heinrich T, Wegener A, Grädler U, Bandeiras TM, Schwarz D, Sousa PMF. Biosensors (Basel) 13 913 (2023)
  10. Halo Library, a Tool for Rapid Identification of Ligand Binding Sites on Proteins Using Crystallographic Fragment Screening. Chopra A, Bauman JD, Ruiz FX, Arnold E. J Med Chem 66 6013-6024 (2023)
  11. Rational design peptide inhibitors of Cyclophilin D as a potential treatment for acute pancreatitis. Li Y, Liu T, Lai X, Xie H, Tang H, Wu S, Li Y. Medicine (Baltimore) 102 e36188 (2023)


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