2. Academic Validation
  3. Augmentation of the antitumor effects of PARP inhibitors in triple-negative breast cancer via degradation by hydrophobic tagging modulation

Augmentation of the antitumor effects of PARP inhibitors in triple-negative breast cancer via degradation by hydrophobic tagging modulation

  • Eur J Med Chem. 2020 Oct 15:204:112635. doi: 10.1016/j.ejmech.2020.112635.
Ahra Go 1,  Jeong Woon Jang 2,  Woori Lee 3,  Jae Du Ha 1,  Hyun Jin Kim 4,  Hye Jin Nam 5
Affiliations

Affiliations

  • 1 Data Convergence Drug Research Center, Therapeutics and Biotechnology Division, Korea Research Institute of Chemical Technology, Daejeon, 34114, Republic of Korea.
  • 2 Drug Discovery Platform Technology Research Center, Therapeutics and Biotechnology Division, Korea Research Institute of Chemical Technology, Daejeon, 34114, Republic of Korea.
  • 3 Data Convergence Drug Research Center, Therapeutics and Biotechnology Division, Korea Research Institute of Chemical Technology, Daejeon, 34114, Republic of Korea; Department of New Drug Discovery and Development, Chungnam National University, 99 Daehak-ro, Yuseong-gu, Daejeon, 305-764, Republic of Korea.
  • 4 Data Convergence Drug Research Center, Therapeutics and Biotechnology Division, Korea Research Institute of Chemical Technology, Daejeon, 34114, Republic of Korea; Department of New Drug Discovery and Development, Chungnam National University, 99 Daehak-ro, Yuseong-gu, Daejeon, 305-764, Republic of Korea. Electronic address: hyunjin@krict.re.kr.
  • 5 Drug Discovery Platform Technology Research Center, Therapeutics and Biotechnology Division, Korea Research Institute of Chemical Technology, Daejeon, 34114, Republic of Korea. Electronic address: hjnam@krict.re.kr.
PMID: 32726747 DOI: 10.1016/j.ejmech.2020.112635
Abstract

Triple-negative breast Cancer (TNBC) has an aggressive phenotype and poor prognosis due to the lack of specific targeted treatments. The development of an effective therapeutic strategy with a novel mechanism is essential for TNBC management. Olaparib, a PARP Inhibitor, has been approved for the treatment of breast or ovarian Cancer patients with breast Cancer gene 1/2 (BRCA1/2) mutations. Here, we report the development of a small molecule targeting PARP1 based on the hydrophobic tagging (HyT) method. Targeted protein misfolding and consequent degradation are caused by HyT. Hydrophobic-tagged olaparib induces the proteasome-dependent degradation of PARP1 and shows enhanced antitumor effects compared to olaparib in TNBC cells. In addition, hydrophobic-tagged olaparib causes ER stress-related unfolded protein response (UPR), Autophagy, and Apoptosis. These results point towards encouraging prospects for chemically modifying approved drugs that not only exhibit superior effects compared to those of the original drugs by triggering novel mechanisms but also provide great feasibility in the translational scenario.

Keywords

Hydrophobic tagging method; Olaparib; Protein degradation; TNBC; Unfolded protein response (UPR).

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