Atul D Jain1, Haranatha Potteti2, Benjamin G Richardson1, Laura Kingsley3, Julia P Luciano4, Aya F Ryuzoji4, Hyun Lee1, Aleksej Krunic1, Andrew D Mesecar5, Sekhar P Reddy6, Terry W Moore7. 1. Department of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, University of Illinois at Chicago, Chicago, IL 60612, USA. 2. Department of Pediatrics, College of Medicine, University of Illinois at Chicago, Chicago, IL 60612, USA. 3. Center for Cancer Research, Purdue University, West Lafayette, IN 47907, USA. 4. Department of Biological Sciences Purdue University, West Lafayette, IN 47907, USA. 5. Department of Biological Sciences Purdue University, West Lafayette, IN 47907, USA; Center for Cancer Research, Purdue University, West Lafayette, IN 47907, USA. 6. Department of Pediatrics, College of Medicine, University of Illinois at Chicago, Chicago, IL 60612, USA; University of Illinois Cancer Center, University of Illinois at Chicago, Chicago, IL 60612, USA. 7. Department of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, University of Illinois at Chicago, Chicago, IL 60612, USA; University of Illinois Cancer Center, University of Illinois at Chicago, Chicago, IL 60612, USA. Electronic address: twmoore@uic.edu.
Abstract
Activation of the transcription factor Nrf2 has been posited to be a promising therapeutic strategy in a number of inflammatory and oxidative stress diseases due to its regulation of detoxifying enzymes. In this work, we have developed a comprehensive structure-activity relationship around a known, naphthalene-based non-electrophilic activator of Nrf2, and we report highly potent non-electrophilic activators of Nrf2. Computational docking analysis of a subset of the compound series demonstrates the importance of water molecule displacement for affinity, and the X-ray structure of di-amide 12e supports the computational analysis. One of the best compounds, acid 16b, has an IC50 of 61 nM in a fluorescence anisotropy assay and a Kd of 120 nM in a surface plasmon resonance assay. Additionally, we demonstrate that the ethyl ester of 16b is an efficacious inducer of Nrf2 target genes, exhibiting ex vivo efficacy similar to the well-known electrophilic activator, sulforaphane.
Activation of the transcription factor Nrf2 has been posited to be a promising therapeutic strategy in a number of inflammatory and oxidative n class="Disease">stress diseases due to its regulation of detoxifying enzymes. In this work, we have developed a comprehensive structure-activity relationship around a known, naphthalene-based non-electrophilic activator of Nrf2, and we report highly potent non-electrophilic activators of Nrf2. Computational docking analysis of a subset of the compound series demonstrates the importance of water molecule displacement for affinity, and the X-ray structure of di-amide 12e supports the computational analysis. One of the best compounds, acid 16b, has an IC50 of 61 nM in a fluorescence anisotropy assay and a Kd of 120 nM in a surface plasmon resonance assay. Additionally, we demonstrate that the ethyl ester of 16b is an efficacious inducer of Nrf2 target genes, exhibiting ex vivo efficacy similar to the well-known electrophilic activator, sulforaphane.
Authors: Thomas A Halgren; Robert B Murphy; Richard A Friesner; Hege S Beard; Leah L Frye; W Thomas Pollard; Jay L Banks Journal: J Med Chem Date: 2004-03-25 Impact factor: 7.446
Authors: Richard A Friesner; Jay L Banks; Robert B Murphy; Thomas A Halgren; Jasna J Klicic; Daniel T Mainz; Matthew P Repasky; Eric H Knoll; Mee Shelley; Jason K Perry; David E Shaw; Perry Francis; Peter S Shenkin Journal: J Med Chem Date: 2004-03-25 Impact factor: 7.446
Authors: Richard A Friesner; Robert B Murphy; Matthew P Repasky; Leah L Frye; Jeremy R Greenwood; Thomas A Halgren; Paul C Sanschagrin; Daniel T Mainz Journal: J Med Chem Date: 2006-10-19 Impact factor: 7.446
Authors: Ling Gao; Jiakun Wang; Konjeti R Sekhar; Huiyong Yin; Nicholas F Yared; Scott N Schneider; Soumya Sasi; Timothy P Dalton; Mark E Anderson; Jefferson Y Chan; Jason D Morrow; Michael L Freeman Journal: J Biol Chem Date: 2006-11-25 Impact factor: 5.157
Authors: Mengqi Zhong; Andrew Lynch; Samantha N Muellers; Stefan Jehle; Lingqi Luo; David R Hall; Reina Iwase; James P Carolan; Megan Egbert; Amanda Wakefield; Kristina Streu; Christine M Harvey; Paula C Ortet; Dima Kozakov; Sandor Vajda; Karen N Allen; Adrian Whitty Journal: Biochemistry Date: 2020-01-02 Impact factor: 3.162
Authors: Phillip R Lazzara; Brian P David; Aparna Ankireddy; Benjamin G Richardson; Katherine Dye; Kiira M Ratia; Sekhar P Reddy; Terry W Moore Journal: J Med Chem Date: 2019-11-14 Impact factor: 7.446
Authors: Jesus M Ontoria; Ilaria Biancofiore; Paola Fezzardi; Federica Ferrigno; Esther Torrente; Stefania Colarusso; Elisabetta Bianchi; Matteo Andreini; Alexandros Patsilinakos; Georg Kempf; Martin Augustin; Stefan Steinbacher; Vincenzo Summa; Robert Pacifici; Ignacio Muñoz-Sanjuan; Larry Park; Alberto Bresciani; Celia Dominguez; Leticia Toledo Sherman; Steven Harper Journal: ACS Med Chem Lett Date: 2020-04-03 Impact factor: 4.345
Authors: Benjamin G Richardson; Atul D Jain; Haranatha R Potteti; Phillip R Lazzara; Brian P David; Chandra R Tamatam; Ewelina Choma; Kornelia Skowron; Katherine Dye; Zamia Siddiqui; Yue-Ting Wang; Aleksej Krunic; Sekhar P Reddy; Terry W Moore Journal: J Med Chem Date: 2018-08-31 Impact factor: 7.446
Authors: Phillip R Lazzara; Atul D Jain; Amanda C Maldonado; Benjamin Richardson; Kornelia J Skowron; Brian P David; Zamia Siddiqui; Kiira M Ratia; Terry W Moore Journal: ACS Med Chem Lett Date: 2020-02-19 Impact factor: 4.345