6c42 › Citations

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)
Related entries: 5ufw, 5ufx

Cited: 19 times
EuropePMC logo PMID: 29915250

Abstract

Complex tissue-specific and cell-specific signaling by the estrogen receptor (ER) frequently leads to the development of resistance to endocrine therapy for breast cancer. Pure ER antagonists, which completely lack tissue-specific agonist activity, hold promise for preventing and treating endocrine resistance, however an absence of structural information hinders the development of novel candidates. Here we synthesize a small panel of benzopyrans with variable side chains to identify pure antiestrogens in a uterotrophic assay. We identify OP-1074 as a pure antiestrogen and a selective ER degrader (PA-SERD) that is efficacious in shrinking tumors in a tamoxifen-resistant xenograft model. Biochemical and crystal structure analyses reveal a structure activity relationship implicating the importance of a stereospecific methyl on the pyrrolidine side chain of OP-1074, particularly on helix 12.

Articles - 6c42 mentioned but not cited (1)

  1. 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)


Reviews citing this publication (4)

  1. Next-Generation ERα Inhibitors for Endocrine-Resistant ER+ Breast Cancer. Fanning SW, Greene GL. Endocrinology 160 759-769 (2019)
  2. Pyrrolidine in Drug Discovery: A Versatile Scaffold for Novel Biologically Active Compounds. Li Petri G, Raimondi MV, Spanò V, Holl R, Barraja P, Montalbano A. Top Curr Chem (Cham) 379 34 (2021)
  3. Emerging modes-of-action in drug discovery. Valeur E, Narjes F, Ottmann C, Plowright AT. Medchemcomm 10 1550-1568 (2019)
  4. Evolution of 3-(4-hydroxyphenyl)indoline-2-one as a scaffold for potent and selective anticancer activity. Boudreau MW, Hergenrother PJ. RSC Med Chem 13 711-725 (2022)

Articles citing this publication (14)

  1. A small-molecule activator of the unfolded protein response eradicates human breast tumors in mice. Boudreau MW, Duraki D, Wang L, Mao C, Kim JE, Henn MA, Tang B, Fanning SW, Kiefer J, Tarasow TM, Bruckheimer EM, Moreno R, Mousses S, Greene GL, Roy EJ, Park BH, Fan TM, Nelson ER, Hergenrother PJ, Shapiro DJ. Sci Transl Med 13 eabf1383 (2021)
  2. Lasofoxifene as a potential treatment for therapy-resistant ER-positive metastatic breast cancer. Lainé M, Fanning SW, Chang YF, Green B, Greene ME, Komm B, Kurleto JD, Phung L, Greene GL. Breast Cancer Res 23 54 (2021)
  3. Design and Synthesis of Basic Selective Estrogen Receptor Degraders for Endocrine Therapy Resistant Breast Cancer. Lu Y, Gutgesell LM, Xiong R, Zhao J, Li Y, Rosales CI, Hollas M, Shen Z, Gordon-Blake J, Dye K, Wang Y, Lee S, Chen H, He D, Dubrovyskyii O, Zhao H, Huang F, Lasek AW, Tonetti DA, Thatcher GRJ. J Med Chem 62 11301-11323 (2019)
  4. Discovery of novel natural compound inhibitors targeting estrogen receptor α by an integrated virtual screening strategy. Yu E, Xu Y, Shi Y, Yu Q, Liu J, Xu L. J Mol Model 25 278 (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. Stereospecific lasofoxifene derivatives reveal the interplay between estrogen receptor alpha stability and antagonistic activity in ESR1 mutant breast cancer cells. Hosfield DJ, Weber S, Li NS, Sauvage M, Joiner CF, Hancock GR, Sullivan EA, Ndukwe E, Han R, Cush S, Lainé M, Mader SC, Greene GL, Fanning SW. Elife 11 e72512 (2022)
  7. Combined Estrogen Alpha and Beta Receptor Expression Has a Prognostic Significance for Colorectal Cancer Patients. Topi G, Ghatak S, Satapathy SR, Ehrnström R, Lydrup ML, Sjölander A. Front Med (Lausanne) 9 739620 (2022)
  8. Daidzein Induces Intrinsic Pathway of Apoptosis along with ER α/β Ratio Alteration and ROS Production. Kumar V, Chauhan SS. Asian Pac J Cancer Prev 22 603-610 (2021)
  9. Ligand-Based Drug Design: Synthesis and Biological Evaluation of Substituted Benzoin Derivatives as Potential Antitumor Agents. Sabbah DA, Ibrahim AH, Talib WH, Alqaisi KM, Sweidan K, Bardaweel SK, Sheikha GA, Zhong HA, Al-Shalabi E, Khalaf RA, Mubarak MS. Med Chem 15 417-429 (2019)
  10. Activators of the Anticipatory Unfolded Protein Response with Enhanced Selectivity for Estrogen Receptor Positive Breast Cancer. Boudreau MW, Mulligan MP, Shapiro DJ, Fan TM, Hergenrother PJ. J Med Chem 65 3894-3912 (2022)
  11. Structural, Thermodynamic, and Kinetic Traits of Antiestrogen-Compounds Selectively Targeting the Y537S Mutant Estrogen Receptor α Transcriptional Activity in Breast Cancer Cell Lines. Pavlin M, Gelsomino L, Barone I, Spinello A, Catalano S, Andò S, Magistrato A. Front Chem 7 602 (2019)
  12. Heterodimeric GW7604 Derivatives: Modification of the Pharmacological Profile by Additional Interactions at the Coactivator Binding Site. Knox AK, Kalchschmid C, Schuster D, Gaggia F, Gust R. J Med Chem 64 5766-5786 (2021)
  13. 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)
  14. Unconventional isoquinoline-based SERMs elicit fulvestrant-like transcriptional programs in ER+ breast cancer cells. Hancock GR, Young KS, Hosfield DJ, Joiner C, Sullivan EA, Yildiz Y, Lainé M, Greene GL, Fanning SW. NPJ Breast Cancer 8 130 (2022)


Quick links