2. Academic Validation
  3. Synthesis and structure activity relationship of the first class of LXR inverse agonists

Synthesis and structure activity relationship of the first class of LXR inverse agonists

  • Bioorg Chem. 2022 Feb;119:105540. doi: 10.1016/j.bioorg.2021.105540.
Bahaa Elgendy 1,  Kristine Griffett 2,  Lamees Hegazy 2,  Paolo Di Fruscia 3,  Kirby Sample 4,  Emmalie Schoepke 5,  Theodore M Kamenecka 6,  Thomas P Burris 7
Affiliations

Affiliations

  • 1 Center for Clinical Pharmacology, Washington University School of Medicine and University of Health Sciences and Pharmacy, St. Louis, MO 63110, USA; Department of Anesthesiology, Washington University School of Medicine, St. Louis, MO 63110, USA; Chemistry Department, Faculty of Science, Benha University, Benha 13518, Egypt. Electronic address: belgendy@wustl.edu.
  • 2 Center for Clinical Pharmacology, Washington University School of Medicine and University of Health Sciences and Pharmacy, St. Louis, MO 63110, USA.
  • 3 Hit Discovery, Discovery Sciences, R&D, AstraZeneca, Cambridge CB4 0WG, United Kingdom.
  • 4 Center for Clinical Pharmacology, Washington University School of Medicine and University of Health Sciences and Pharmacy, St. Louis, MO 63110, USA; Department of Anesthesiology, Washington University School of Medicine, St. Louis, MO 63110, USA.
  • 5 Department of Pharmacology and Physiology, Saint Louis University School of Medicine, St. Louis, MO 63104, USA.
  • 6 The Scripps Research Institute, Scripps Florida, Department of Molecular Medicine, 130 Scripps Way #A2A, Jupiter, FL 33458, USA.
  • 7 Center for Clinical Pharmacology, Washington University School of Medicine and University of Health Sciences and Pharmacy, St. Louis, MO 63110, USA; Department of Anesthesiology, Washington University School of Medicine, St. Louis, MO 63110, USA. Electronic address: tburris@wustl.edu.
PMID: 34902646 DOI: 10.1016/j.bioorg.2021.105540
Abstract

Liver X Receptors (LXRs) are members of the nuclear receptor family, and they play significant role in lipid and Cholesterol metabolism. Moreover, they are key regulators of several inflammatory pathways. Pharmacological modulation of LXRs holds great potential in treatment of metabolic diseases, neurodegenerative diseases, and Cancer. We were the first group to identify LXR inverse agonists SR9238 (6) and SR9243 (7) and demonstrate their potential utility in treating liver diseases and Cancer. Here, we present the results of structure-activity relationship (SAR) studies, based around SR9238 (6) and SR9243 (7). This study led to identification of 16, 17, 19, and 38, which were more potent inverse agonists than SR9238 (6) and SR9243 (7) and inhibited expression of the fatty acid synthase gene in DU145 cells. We previously demonstrated that inhibition of FASN is correlated to the Anticancer activity of SR9243 (7) and this suggests that new inverse agonists have great potential as Anticancer agents. We identified compounds with distinct selectivity toward both LXR isoforms, which can be excellent tools to study the pharmacology of both isoforms. We employed molecular dynamic (MD) simulations to better understand the molecular mechanism underlying inverse agonist activity and to guide our future design.

Keywords

Anticancer; Chemical Probes; LXR inverse agonists; MD Simulations; Tertiary sulfonamides.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-143259
    99.86%, LXR Inverse Agonist
    LXR