5kcc › Citations

Full antagonism of the estrogen receptor without a prototypical ligand side chain.

Srinivasan S, Nwachukwu JC, Bruno NE, Dharmarajan V, Goswami D, Kastrati I, Novick S, Nowak J, Cavett V, Zhou HB, Boonmuen N, Zhao Y, Min J, Frasor J, Katzenellenbogen BS, Griffin PR, Katzenellenbogen JA, Nettles KW
Nat Chem Biol 13 111-118 (2017)
Related entries: 5kcd, 5kce, 5kcf, 5kct, 5kcu, 5kcw, 5kd9

Cited: 22 times
EuropePMC logo PMID: 27870835

Abstract

Resistance to endocrine therapies remains a major clinical problem for the treatment of estrogen receptor-α (ERα)-positive breast cancer. On-target side effects limit therapeutic compliance and use for chemoprevention, highlighting an unmet need for new therapies. Here we present a full-antagonist ligand series lacking the prototypical ligand side chain that has been universally used to engender antagonism of ERα through poorly understood structural mechanisms. A series of crystal structures and phenotypic assays reveal a structure-based design strategy with separate design elements for antagonism and degradation of the receptor, and access to a structurally distinct space for further improvements in ligand design. Understanding structural rules that guide ligands to produce diverse ERα-mediated phenotypes has broad implications for the treatment of breast cancer and other estrogen-sensitive aspects of human health including bone homeostasis, energy metabolism, and autoimmunity.

Articles - 5kcc mentioned but not cited (1)

  1. Full antagonism of the estrogen receptor without a prototypical ligand side chain. Srinivasan S, Nwachukwu JC, Bruno NE, Dharmarajan V, Goswami D, Kastrati I, Novick S, Nowak J, Cavett V, Zhou HB, Boonmuen N, Zhao Y, Min J, Frasor J, Katzenellenbogen BS, Griffin PR, Katzenellenbogen JA, Nettles KW. Nat Chem Biol 13 111-118 (2017)


Reviews citing this publication (4)

  1. Structural underpinnings of oestrogen receptor mutations in endocrine therapy resistance. Katzenellenbogen JA, Mayne CG, Katzenellenbogen BS, Greene GL, Chandarlapaty S. Nat Rev Cancer 18 377-388 (2018)
  2. An overview of hydrogen deuterium exchange mass spectrometry (HDX-MS) in drug discovery. Masson GR, Jenkins ML, Burke JE. Expert Opin Drug Discov 12 981-994 (2017)
  3. Next-Generation ERα Inhibitors for Endocrine-Resistant ER+ Breast Cancer. Fanning SW, Greene GL. Endocrinology 160 759-769 (2019)
  4. Recent progress in selective estrogen receptor downregulators (SERDs) for the treatment of breast cancer. Shagufta, Ahmad I, Mathew S, Rahman S. RSC Med Chem 11 438-454 (2020)

Articles citing this publication (17)

  1. A Computational Assay of Estrogen Receptor α Antagonists Reveals the Key Common Structural Traits of Drugs Effectively Fighting Refractory Breast Cancers. Pavlin M, Spinello A, Pennati M, Zaffaroni N, Gobbi S, Bisi A, Colombo G, Magistrato A. Sci Rep 8 649 (2018)
  2. Specific stereochemistry of OP-1074 disrupts estrogen receptor alpha helix 12 and confers pure antiestrogenic activity. Fanning SW, Hodges-Gallagher L, Myles DC, Sun R, Fowler CE, Plant IN, Green BD, Harmon CL, Greene GL, Kushner PJ. Nat Commun 9 2368 (2018)
  3. PPARγ in Complex with an Antagonist and Inverse Agonist: a Tumble and Trap Mechanism of the Activation Helix. Frkic RL, Marshall AC, Blayo AL, Pukala TL, Kamenecka TM, Griffin PR, Bruning JB. iScience 5 69-79 (2018)
  4. Pocket similarity identifies selective estrogen receptor modulators as microtubule modulators at the taxane site. Lo YC, Cormier O, Liu T, Nettles KW, Katzenellenbogen JA, Stearns T, Altman RB. Nat Commun 10 1033 (2019)
  5. Dual-mechanism estrogen receptor inhibitors. Min J, Nwachukwu JC, Min CK, Njeri JW, Srinivasan S, Rangarajan ES, Nettles CC, Sanabria Guillen V, Ziegler Y, Yan S, Carlson KE, Hou Y, Kim SH, Novick S, Pascal BD, Houtman R, Griffin PR, Izard T, Katzenellenbogen BS, Katzenellenbogen JA, Nettles KW. Proc Natl Acad Sci U S A 118 e2101657118 (2021)
  6. Adamantyl Antiestrogens with Novel Side Chains Reveal a Spectrum of Activities in Suppressing Estrogen Receptor Mediated Activities in Breast Cancer Cells. Min J, Guillen VS, Sharma A, Zhao Y, Ziegler Y, Gong P, Mayne CG, Srinivasan S, Kim SH, Carlson KE, Nettles KW, Katzenellenbogen BS, Katzenellenbogen JA. J Med Chem 60 6321-6336 (2017)
  7. Dual functional small molecule fluorescent probes for image-guided estrogen receptor-specific targeting coupled potent antiproliferative potency for breast cancer therapy. Yang L, Hu Z, Luo J, Tang C, Zhang S, Ning W, Dong C, Huang J, Liu X, Zhou HB. Bioorg Med Chem 25 3531-3539 (2017)
  8. Estrogenicity of halogenated bisphenol A: in vitro and in silico investigations. Zhang J, Li T, Wang T, Yuan C, Zhong S, Guan T, Li Z, Wang Y, Yu H, Luo Q, Wang Y, Zhang T. Arch Toxicol 92 1215-1223 (2018)
  9. Rational design and optimization of selenophenes with basic side chains as novel potent selective estrogen receptor modulators (SERMs) for breast cancer therapy. Luo J, Hu Z, Xiao Y, Yang T, Dong C, Huang J, Zhou HB. Medchemcomm 8 1485-1497 (2017)
  10. Discovery of novel oestrogen receptor α agonists and antagonists by screening a revisited privileged structure moiety for nuclear receptors. Masuya T, Iwamoto M, Liu X, Matsushima A. Sci Rep 9 9954 (2019)
  11. Human Estrogen Receptor Alpha Antagonists, Part 3: 3-D Pharmacophore and 3-D QSAR Guided Brefeldin A Hit-to-Lead Optimization toward New Breast Cancer Suppressants. Kurtanović N, Tomašević N, Matić S, Proia E, Sabatino M, Antonini L, Mladenović M, Ragno R. Molecules 27 2823 (2022)
  12. Structural insight into the antagonistic action of diarylheptanoid on human estrogen receptor alpha. Geetha Rani Y, Lakshmi BS. J Biomol Struct Dyn 37 1189-1203 (2019)
  13. Corrigendum: Full antagonism of the estrogen receptor without a prototypical ligand side chain. Srinivasan S, Nwachukwu JC, Bruno NE, Dharmarajan V, Goswami D, Kastrati I, Novick S, Nowak J, Cavett V, Zhou HB, Boonmuen N, Zhao Y, Min J, Frasor J, Katzenellenbogen BS, Griffin PR, Katzenellenbogen JA, Nettles KW. Nat Chem Biol 13 691 (2017)
  14. Exploring Ligand Binding Domain Dynamics in the NRs Superfamily. D'Arrigo G, Autiero I, Gianquinto E, Siragusa L, Baroni M, Cruciani G, Spyrakis F. Int J Mol Sci 23 8732 (2022)
  15. Discovery of novel covalent selective estrogen receptor degraders against endocrine-resistant breast cancer. Wang Y, Min J, Deng X, Feng T, Hu H, Guo X, Cheng Y, Xie B, Yang Y, Chen CC, Guo RT, Dong C, Zhou HB. Acta Pharm Sin B 13 4963-4982 (2023)
  16. Erratum: Full antagonism of the estrogen receptor without a prototypical ligand side chain. Srinivasan S, Nwachukwu JC, Bruno NE, Dharmarajan V, Goswami D, Kastrati I, Novick S, Nowak J, Cavett V, Zhou HB, Boonmuen N, Zhao Y, Min J, Frasor J, Katzenellenbogen BS, Griffin PR, Katzenellenbogen JA, Nettles KW. Nat Chem Biol 13 691 (2017)
  17. Fulvestrant in management of hormone receptor-positive metastatic breast cancer. Shafaee MN, Ellis MJ. Future Oncol 14 1789-1800 (2018)


Quick links