5i4v › Citations

Discovery of a Novel, Orally Efficacious Liver X Receptor (LXR) β Agonist.

Zheng Y, Zhuang L, Fan KY, Tice CM, Zhao W, Dong C, Lotesta SD, Leftheris K, Lindblom PR, Liu Z, Shimada J, Noto PB, Meng S, Hardy A, Howard L, Krosky P, Guo J, Lipinski K, Kandpal G, Bukhtiyarov Y, Zhao Y, Lala D, Van Orden R, Zhou J, Chen G, Wu Z, McKeever BM, McGeehan GM, Gregg RE, Claremon DA, Singh SB
J Med Chem 59 3264-71 (2016)
Cited: 11 times
EuropePMC logo PMID: 26990539

Abstract

This article describes the application of Contour to the design and discovery of a novel, potent, orally efficacious liver X receptor β (LXRβ) agonist (17). Contour technology is a structure-based drug design platform that generates molecules using a context perceptive growth algorithm guided by a contact sensitive scoring function. The growth engine uses binding site perception and programmable growth capability to create drug-like molecules by assembling fragments that naturally complement hydrophilic and hydrophobic features of the protein binding site. Starting with a crystal structure of LXRβ and a docked 2-(methylsulfonyl)benzyl alcohol fragment (6), Contour was used to design agonists containing a piperazine core. Compound 17 binds to LXRβ with high affinity and to LXRα to a lesser extent, and induces the expression of LXR target genes in vitro and in vivo. This molecule served as a starting point for further optimization and generation of a candidate which is currently in human clinical trials for treating atopic dermatitis.

Reviews citing this publication (7)

  1. Liver X receptors in lipid signalling and membrane homeostasis. Wang B, Tontonoz P. Nat Rev Endocrinol 14 452-463 (2018)
  2. The challenges and promise of targeting the Liver X Receptors for treatment of inflammatory disease. Fessler MB. Pharmacol Ther 181 1-12 (2018)
  3. Ligands of Therapeutic Utility for the Liver X Receptors. Komati R, Spadoni D, Zheng S, Sridhar J, Riley KE, Wang G. Molecules 22 E88 (2017)
  4. Liver X receptors: from cholesterol regulation to neuroprotection-a new barrier against neurodegeneration in amyotrophic lateral sclerosis? Mouzat K, Raoul C, Polge A, Kantar J, Camu W, Lumbroso S. Cell Mol Life Sci 73 3801-3808 (2016)
  5. Remembering your A, B, C's: Alzheimer's disease and ABCA1. Lewandowski CT, Laham MS, Thatcher GRJ. Acta Pharm Sin B 12 995-1018 (2022)
  6. Conformational control in structure-based drug design. Zheng Y, Tice CM, Singh SB. Bioorg Med Chem Lett 27 2825-2837 (2017)
  7. Role of the liver X receptors in skin physiology: Putative pharmacological targets in human diseases. Ouedraogo ZG, Fouache A, Trousson A, Baron S, Lobaccaro JA. Chem Phys Lipids 207 59-68 (2017)

Articles citing this publication (4)

  1. Development of Tetrachlorophthalimides as Liver X Receptor β (LXRβ)-Selective Agonists. Nomura S, Endo-Umeda K, Makishima M, Hashimoto Y, Ishikawa M. ChemMedChem 11 2347-2360 (2016)
  2. Mutational dynamics and immune evasion in diffuse large B-cell lymphoma explored in a relapse-enriched patient series. Wise JF, Nakken S, Steen CB, Vodák D, Trøen G, Johannessen B, Lingjærde OC, Hilden V, Blaker YN, Bai B, Aasheim LB, Pasanen A, Lorenz S, Sveen A, Lothe RA, Myklebost O, Leppä S, Meza-Zepeda LA, Beiske K, Lawrence MS, Hovig E, Myklebust JH, Smeland EB, Holte H. Blood Adv 4 1859-1866 (2020)
  3. Brain penetrant liver X receptor (LXR) modulators based on a 2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazole core. Tice CM, Noto PB, Fan KY, Zhao W, Lotesta SD, Dong C, Marcus AP, Zheng YJ, Chen G, Wu Z, Van Orden R, Zhou J, Bukhtiyarov Y, Zhao Y, Lipinski K, Howard L, Guo J, Kandpal G, Meng S, Hardy A, Krosky P, Gregg RE, Leftheris K, McKeever BM, Singh SB, Lala D, McGeehan GM, Zhuang L, Claremon DA. Bioorg Med Chem Lett 26 5044-5050 (2016)
  4. Synergetic Effect of rHDL and LXR Agonist on Reduction of Atherosclerosis in Mice. Morin EE, Guo Y, He H, Yuan W, Souery WN, Fawaz MV, Chen YE, Schwendeman A. Front Pharmacol 11 513031 (2020)


Quick links