Mohammad A Khanfar1, Luisa Quinti2, Hua Wang3, Soo Hyuk Choi3, Aleksey G Kazantsev4, Richard B Silverman5. 1. Department of Chemistry, Department of Molecular Biosciences, Chemistry of Life Processes Institute, Center for Molecular Innovation and Drug Discovery, Northwestern University, 2145 Sheridan Road, Evanston, IL 60208-3113, USA; Department of Pharmaceutical Sciences, The University of Jordan, Amman, Jordan. 2. Department of Neurology, Harvard Medical School and Massachusetts General Hospital, Charlestown, MA 02129-4404, USA. 3. Department of Chemistry, Department of Molecular Biosciences, Chemistry of Life Processes Institute, Center for Molecular Innovation and Drug Discovery, Northwestern University, 2145 Sheridan Road, Evanston, IL 60208-3113, USA. 4. Department of Neurology, Harvard Medical School and Massachusetts General Hospital, Charlestown, MA 02129-4404, USA. Electronic address: akazantsev@mgh.harvard.edu. 5. Department of Chemistry, Department of Molecular Biosciences, Chemistry of Life Processes Institute, Center for Molecular Innovation and Drug Discovery, Northwestern University, 2145 Sheridan Road, Evanston, IL 60208-3113, USA. Electronic address: Agman@chem.northwestern.edu.
Abstract
Inhibitors of sirtuin-2 deacetylase (SIRT2) have been shown to be protective in various models of Huntington's disease (HD) by decreasing polyglutamine aggregation, a hallmark of HD pathology. The present study was directed at optimizing the potency of SIRT2 inhibitors containing the neuroprotective sulfobenzoic acid scaffold and improving their pharmacology. To achieve that goal, 176 analogues were designed, synthesized, and tested in deacetylation assays against the activities of major human sirtuins SIRT1-3. This screen yielded 15 compounds with enhanced potency for SIRT2 inhibition and 11 compounds having SIRT2 inhibition equal to reference compound AK-1. The newly synthesized compounds also demonstrated higher SIRT2 selectivity over SIRT1 and SIRT3. These candidates were subjected to a dose-response bioactivity assay, measuring an increase in α-tubulin K40 acetylation in two neuronal cell lines, which yielded five compounds bioactive in both cell lines and eight compounds bioactive in at least one of the cell lines tested. These bioactive compounds were subsequently tested in a tertiary polyglutamine aggregation assay, which identified five inhibitors. ADME properties of the bioactive SIRT2 inhibitors were assessed, which revealed a significant improvement of the pharmacological properties of the new entities, reaching closer to the goal of a clinically-viable candidate.
Inhibitors of sirtuin-2 deacetylase (n class="Gene">SIRT2) have been shown to be protective in various models of Huntington's disease (HD) by decreasing polyglutamine aggregation, a hallmark of HD pathology. The present study was directed at optimizing the potency of SIRT2 inhibitors containing the neuroprotective sulfobenzoic acid scaffold and improving their pharmacology. To achieve that goal, 176 analogues were designed, synthesized, and tested in deacetylation assays against the activities of major human sirtuins SIRT1-3. This screen yielded 15 compounds with enhanced potency for SIRT2 inhibition and 11 compounds having SIRT2 inhibition equal to reference compound AK-1. The newly synthesized compounds also demonstrated higher SIRT2 selectivity over SIRT1 and SIRT3. These candidates were subjected to a dose-response bioactivity assay, measuring an increase in α-tubulin K40 acetylation in two neuronal cell lines, which yielded five compounds bioactive in both cell lines and eight compounds bioactive in at least one of the cell lines tested. These bioactive compounds were subsequently tested in a tertiary polyglutamine aggregation assay, which identified five inhibitors. ADME properties of the bioactive SIRT2 inhibitors were assessed, which revealed a significant improvement of the pharmacological properties of the new entities, reaching closer to the goal of a clinically-viable candidate.
Authors: Ruth Luthi-Carter; David M Taylor; Judit Pallos; Emmanuel Lambert; Allison Amore; Alex Parker; Hilary Moffitt; Donna L Smith; Heike Runne; Ozgun Gokce; Alexandre Kuhn; Zhongmin Xiang; Michele M Maxwell; Steven A Reeves; Gillian P Bates; Christian Neri; Leslie M Thompson; J Lawrence Marsh; Aleksey G Kazantsev Journal: Proc Natl Acad Sci U S A Date: 2010-04-08 Impact factor: 11.205
Authors: Tero Huhtiniemi; Tiina Suuronen; Valtteri M Rinne; Carsten Wittekindt; Maija Lahtela-Kakkonen; Elina Jarho; Erik A A Wallén; Antero Salminen; Antti Poso; Jukka Leppänen Journal: J Med Chem Date: 2008-07-22 Impact factor: 7.446
Authors: David M Taylor; Uma Balabadra; Zhongmin Xiang; Ben Woodman; Sarah Meade; Allison Amore; Michele M Maxwell; Steven Reeves; Gillian P Bates; Ruth Luthi-Carter; Philip A S Lowden; Aleksey G Kazantsev Journal: ACS Chem Biol Date: 2011-03-09 Impact factor: 5.100
Authors: Marcus Freitag; Jörg Schemies; Tim Larsen; Khattab El Gaghlab; Felix Schulz; Tobias Rumpf; Manfred Jung; Andreas Link Journal: Bioorg Med Chem Date: 2011-01-22 Impact factor: 3.641
Authors: Mohammad A Khanfar; Luisa Quinti; Hua Wang; Johnathan Nobles; Aleksey G Kazantsev; Richard B Silverman Journal: ACS Med Chem Lett Date: 2015-03-26 Impact factor: 4.345
Authors: Arno Verlee; Thomas Heugebaert; Tom van der Meer; Pavel I Kerchev; Frank Van Breusegem; Christian V Stevens Journal: Beilstein J Org Chem Date: 2017-02-16 Impact factor: 2.883
Authors: Michael Schnekenburger; Véronique Mathieu; Florence Lefranc; Jun Young Jang; Marco Masi; Anake Kijjoa; Antonio Evidente; Hyun-Jung Kim; Robert Kiss; Mario Dicato; Byung Woo Han; Marc Diederich Journal: Molecules Date: 2018-02-05 Impact factor: 4.411