2. Academic Validation
  3. Discovery of novel anti-breast cancer agents derived from deguelin as inhibitors of heat shock protein 90 (HSP90)

Discovery of novel anti-breast cancer agents derived from deguelin as inhibitors of heat shock protein 90 (HSP90)

  • Bioorg Med Chem Lett. 2020 Sep 1;30(17):127374. doi: 10.1016/j.bmcl.2020.127374.
Cong-Truong Nguyen 1,  Jihyae Ann 1,  Raghaba Sahu 1,  Woong Sub Byun 1,  Sangkook Lee 1,  Gibeom Nam 2,  Hyun-Ju Park 2,  Soeun Park 3,  Yoon-Jae Kim 4,  Ji Young Kim 5,  Jae Hong Seo 3,  Jeewoo Lee 1
Affiliations

Affiliations

  • 1 College of Pharmacy, Seoul National University, Seoul 08826, Republic of Korea.
  • 2 School of Pharmacy, Sungkyunkwan University, Suwon, Gyeonggi-do 16419, Republic of Korea.
  • 3 Division of Medical Oncology, Department of Internal Medicine, Korea University College of Medicine, Korea University, Seoul 152-703, Republic of Korea; Brain Korea 21 Program for Biomedical Science, Korea University College of Medicine, Korea University, Seoul 152-703, Republic of Korea.
  • 4 Division of Medical Oncology, Department of Internal Medicine, Korea University College of Medicine, Korea University, Seoul 152-703, Republic of Korea; Department of Biomedical Research Center, Korea University Guro Hospital, Korea University, Seoul 152-703, Republic of Korea.
  • 5 Division of Medical Oncology, Department of Internal Medicine, Korea University College of Medicine, Korea University, Seoul 152-703, Republic of Korea.
PMID: 32738983 DOI: 10.1016/j.bmcl.2020.127374
Abstract

A series of O-substituted analogues of the B,C-ring truncated scaffold of deguelin were designed as C-terminal inhibitors of heat shock protein 90 (HSP90) and investigated as novel antiproliferative agents against HER2-positive breast Cancer. Among the synthesized compounds, compound 80 exhibited significant inhibition in both trastuzumab-sensitive and trastuzumab-resistant breast Cancer cells, whereas compound 80 did not show any cytotoxicity in normal cells. Compound 80 markedly downregulated the expression of the major client proteins of HSP90 in both cell types, indicating that the cytotoxicity of 80 in breast Cancer cells is attributed to the destabilization and inactivation of HSP90 client proteins and that HSP90 inhibition represents a promising strategy to overcome trastuzumab resistance. A molecular docking study of 80 with the homology model of a HSP90 homodimer showed that 80 fit nicely in the C-terminal domain with a higher electrostatic complementary score than that of ATP.

Keywords

Deguelin; HER2-positive breast cancer; Heat shock protein 90; Human epidermal growth factor receptor 2.

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