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Tailoring small molecules for an allosteric site on procaspase-6.

Murray J, Giannetti AM, Steffek M, Gibbons P, Hearn BR, Cohen F, Tam C, Pozniak C, Bravo B, Lewcock J, Jaishankar P, Ly CQ, Zhao X, Tang Y, Chugha P, Arkin MR, Flygare J, Renslo AR
ChemMedChem 9 73-7, 2 (2014)
Related entries: 4n6g, 4n7j, 4n7m, 4nbk, 4nbl, 4nbn

Cited: 13 times
EuropePMC logo PMID: 24259468

Abstract

Although they represent attractive therapeutic targets, caspases have so far proven recalcitrant to the development of drugs targeting the active site. Allosteric modulation of caspase activity is an alternate strategy that potentially avoids the need for anionic and electrophilic functionality present in most active-site inhibitors. Caspase-6 has been implicated in neurodegenerative disease, including Huntington's and Alzheimer's diseases. Herein we describe a fragment-based lead discovery effort focused on caspase-6 in its active and zymogen forms. Fragments were identified for procaspase-6 using surface plasmon resonance methods and subsequently shown by X-ray crystallography to bind a putative allosteric site at the dimer interface. A fragment-merging strategy was employed to produce nanomolar-affinity ligands that contact residues in the L2 loop at the dimer interface, significantly stabilizing procaspase-6. Because rearrangement of the L2 loop is required for caspase-6 activation, our results suggest a strategy for the allosteric control of caspase activation with drug-like small molecules.

Reviews - 4n5d mentioned but not cited (1)

  1. Small Molecule Active Site Directed Tools for Studying Human Caspases. Poreba M, Szalek A, Kasperkiewicz P, Rut W, Salvesen GS, Drag M. Chem Rev 115 12546-12629 (2015)

Articles - 4n5d mentioned but not cited (2)

  1. Caspase-6 Undergoes a Distinct Helix-Strand Interconversion upon Substrate Binding. Dagbay KB, Bolik-Coulon N, Savinov SN, Hardy JA. J Biol Chem 292 4885-4897 (2017)
  2. Activation of Caspase-6 Is Promoted by a Mutant Huntingtin Fragment and Blocked by an Allosteric Inhibitor Compound. Ehrnhoefer DE, Skotte NH, Reinshagen J, Qiu X, Windshügel B, Jaishankar P, Ladha S, Petina O, Khankischpur M, Nguyen YTN, Caron NS, Razeto A, Meyer Zu Rheda M, Deng Y, Huynh KT, Wittig I, Gribbon P, Renslo AR, Geffken D, Gul S, Hayden MR. Cell Chem Biol 26 1295-1305.e6 (2019)


Reviews citing this publication (2)

  1. Twenty years on: the impact of fragments on drug discovery. Erlanson DA, Fesik SW, Hubbard RE, Jahnke W, Jhoti H. Nat Rev Drug Discov 15 605-619 (2016)
  2. Activation and regulation of caspase-6 and its role in neurodegenerative diseases. Wang XJ, Cao Q, Zhang Y, Su XD. Annu Rev Pharmacol Toxicol 55 553-572 (2015)

Articles citing this publication (8)

  1. Caspase vinyl sulfone small molecule inhibitors prevent axonal degeneration in human neurons and reverse cognitive impairment in Caspase-6-overexpressing mice. Pakavathkumar P, Noël A, Lecrux C, Tubeleviciute-Aydin A, Hamel E, Ahlfors JE, LeBlanc AC. Mol Neurodegener 12 22 (2017)
  2. Identification of Allosteric Inhibitors against Active Caspase-6. Tubeleviciute-Aydin A, Beautrait A, Lynham J, Sharma G, Gorelik A, Deny LJ, Soya N, Lukacs GL, Nagar B, Marinier A, LeBlanc AC. Sci Rep 9 5504 (2019)
  3. Chemoproteomics Using Nucleotide Acyl Phosphates Reveals an ATP Binding Site at the Dimer Interface of Procaspase-6. Okerberg ES, Dagbay KB, Green JL, Soni I, Aban A, Nomanbhoy TK, Savinov SN, Hardy JA, Kozarich JW. Biochemistry 58 5320-5328 (2019)
  4. Integrative X-ray Structure and Molecular Modeling for the Rationalization of Procaspase-8 Inhibitor Potency and Selectivity. Xu JH, Eberhardt J, Hill-Payne B, González-Páez GE, Castellón JO, Cravatt BF, Forli S, Wolan DW, Backus KM. ACS Chem Biol 15 575-586 (2020)
  5. An electrophilic fragment screening for the development of small molecules targeting caspase-2. Cuellar ME, Yang M, Karavadhi S, Zhang YQ, Zhu H, Sun H, Shen M, Hall MD, Patnaik S, Ashe KH, Walters MA, Pockes S. Eur J Med Chem 259 115632 (2023)
  6. Aromatic interactions with heterocycles in water. Tobajas-Curiel G, Sun Q, Sanders JKM, Ballester P, Hunter CA. Chem Sci 14 11131-11140 (2023)
  7. Engaging a Non-catalytic Cysteine Residue Drives Potent and Selective Inhibition of Caspase-6. Van Horn KS, Wang D, Medina-Cleghorn D, Lee PS, Bryant C, Altobelli C, Jaishankar P, Leung KK, Ng RA, Ambrose AJ, Tang Y, Arkin MR, Renslo AR. J Am Chem Soc 145 10015-10021 (2023)
  8. Systematic Study of Heteroarene Stacking Using a Congeneric Set of Molecular Glues for Procaspase-6. Togo T, Tram L, Denton LG, ElHilali-Pollard X, Gu J, Jiang J, Liu C, Zhao Y, Zhao Y, Zheng Y, Zheng Y, Yang J, Fan P, Arkin MR, Härmä H, Sun D, Canan SS, Wheeler SE, Renslo AR. J Med Chem 66 9784-9796 (2023)


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