2. Academic Validation
  3. The C-terminal HSP90 inhibitor NCT-58 kills trastuzumab-resistant breast cancer stem-like cells

The C-terminal HSP90 inhibitor NCT-58 kills trastuzumab-resistant breast cancer stem-like cells

  • Cell Death Discov. 2021 Nov 13;7(1):354. doi: 10.1038/s41420-021-00743-2.
Soeun Park  # 1 2,  Yoon-Jae Kim  # 1 2 3,  Jung Min Park 1 2,  Minsu Park 1 2,  Kee Dal Nam 1 3,  Lee Farrand 4,  Cong-Truong Nguyen 5,  Minh Thanh La 5,  Jihyae Ann 5,  Jeewoo Lee 6,  Ji Young Kim 7 8,  Jae Hong Seo 9 10 11
Affiliations

Affiliations

  • 1 Division of Medical Oncology, Department of Internal Medicine, Korea University College of Medicine, Korea University, Seoul, 152-703, Republic of Korea.
  • 2 Brain Korea 21 Program for Biomedical Science, Korea University College of Medicine, Korea University, Seoul, 152-703, Republic of Korea.
  • 3 Department of Biomedical Research Center, Korea University Guro Hospital, Korea University, Seoul, 08308, Republic of Korea.
  • 4 Adelaide Medical School, Faculty of Health and Medical Sciences, The University of Adelaide, Adelaide, SA, 5000, Australia.
  • 5 Laboratory of Medicinal Chemistry, College of Pharmacy, Seoul National University, Seoul, 08826, Republic of Korea.
  • 6 Laboratory of Medicinal Chemistry, College of Pharmacy, Seoul National University, Seoul, 08826, Republic of Korea. [email protected].
  • 7 Division of Medical Oncology, Department of Internal Medicine, Korea University College of Medicine, Korea University, Seoul, 152-703, Republic of Korea. [email protected].
  • 8 Department of Biomedical Research Center, Korea University Guro Hospital, Korea University, Seoul, 08308, Republic of Korea. [email protected].
  • 9 Division of Medical Oncology, Department of Internal Medicine, Korea University College of Medicine, Korea University, Seoul, 152-703, Republic of Korea. [email protected].
  • 10 Brain Korea 21 Program for Biomedical Science, Korea University College of Medicine, Korea University, Seoul, 152-703, Republic of Korea. [email protected].
  • 11 Department of Biomedical Research Center, Korea University Guro Hospital, Korea University, Seoul, 08308, Republic of Korea. [email protected].
  • # Contributed equally.
PMID: 34775489 DOI: 10.1038/s41420-021-00743-2
Abstract

N-terminal HSP90 inhibitors in development have had issues arising from heat shock response (HSR) induction and off-target effects. We sought to investigate the capacity of NCT-58, a rationally-synthesized C-terminal HSP90 Inhibitor, to kill trastuzumab-resistant HER2-positive breast Cancer stem-like cells. NCT-58 does not induce the HSR due to its targeting of the C-terminal region and elicits anti-tumor activity via the simultaneous downregulation of HER family members as well as inhibition of Akt phosphorylation. NCT-58 kills the rapidly proliferating bulk tumor cells as well as the breast Cancer stem-like population, coinciding with significant reductions in stem/progenitor markers and pluripotent transcription factors. NCT-58 treatment suppressed growth and angiogenesis in a trastuzumab-resistant xenograft model, concomitant with downregulation of ICD-HER2 and HSF-1/HSP70/HSP90. These findings warrant further investigation of NCT-58 to address trastuzumab resistance in heterogeneous HER2-positive cancers.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-145102
    99.82%, HSP90 C-terminal Inhibitor