2. Academic Validation
  3. Design, synthesis and pharmacological evaluation of new PARP1 inhibitors by merging pharmacophores of olaparib and the natural product alantolactone

Design, synthesis and pharmacological evaluation of new PARP1 inhibitors by merging pharmacophores of olaparib and the natural product alantolactone

  • Eur J Med Chem. 2022 Oct 5;240:114574. doi: 10.1016/j.ejmech.2022.114574.
Muzaffar Kayumov 1,  Li Jia 2,  Azizbek Pardaev 1,  Shan-Shan Song 3,  Sharafitdin Mirzaakhmedov 4,  Chunyong Ding 5,  Yong-Jun Cheng 3,  Ruihan Isabella Zhang 6,  Xubin Bao 3,  Ze-Hong Miao 2,  Jin-Xue He 7,  Ao Zhang 8
Affiliations

Affiliations

  • 1 Pharm-X Center, School of Pharmaceutical Sciences, Shanghai Jiao Tong University, Shanghai, 200240, China; State Key Laboratory of Drug Research, Cancer Research Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China; University of Chinese Academy of Sciences, No.19A Yuquan Road, Beijing, 100049, China; Institute of Bioorganic Chemistry of the Academy of Sciences of the Republic of Uzbekistan, Tashkent, 100125, Uzbekistan.
  • 2 State Key Laboratory of Drug Research, Cancer Research Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China; University of Chinese Academy of Sciences, No.19A Yuquan Road, Beijing, 100049, China.
  • 3 State Key Laboratory of Drug Research, Cancer Research Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China.
  • 4 Institute of Bioorganic Chemistry of the Academy of Sciences of the Republic of Uzbekistan, Tashkent, 100125, Uzbekistan.
  • 5 Pharm-X Center, School of Pharmaceutical Sciences, Shanghai Jiao Tong University, Shanghai, 200240, China.
  • 6 WLSA Shanghai Academy, Shanghai, 200433, China.
  • 7 State Key Laboratory of Drug Research, Cancer Research Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China; University of Chinese Academy of Sciences, No.19A Yuquan Road, Beijing, 100049, China. Electronic address: [email protected].
  • 8 Pharm-X Center, School of Pharmaceutical Sciences, Shanghai Jiao Tong University, Shanghai, 200240, China; State Key Laboratory of Drug Research, Cancer Research Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China; University of Chinese Academy of Sciences, No.19A Yuquan Road, Beijing, 100049, China. Electronic address: [email protected].
PMID: 35785724 DOI: 10.1016/j.ejmech.2022.114574
Abstract

Based on the reported synthetic lethality of the combination of PARP Inhibitor olaparib with the natural product alantolactone, we designed several series of new PARP1 inhibitors by structurally merging both compounds into a single hybrid compound. Among them, compounds 20e and 25a displayed not only high biochemical activity (IC50 = 2.99 nM and 5.91 nM vs 11.36 nM), but also higher inhibitory effects against proliferation of BRCA1-deficient UWB1.289 cells than olaparib (IC50 = 0.27 μM and 0.41 μM vs 0.66 μM). Much weak activity was observed in BRCA1 wild-type human fetal lung IMR-90 and WI-38 cells (IC50s > 10 μM). Treatment with compounds 20e and 25a was found to induce increased levels of γH2AX in a concentration-dependent manner in both MDA-MB-436 and Capan-1 cells to a degree comparable with that of olaparib. Further mechanism study indicated that these compounds activated the cell cycle checkpoints, and subsequently induced G2/M arrest and Apoptosis. The results validated that merging PARP inhibitors with other DNA-damage related compounds would produce more potent PARP inhibitors for Anticancer studies. However, the poor aqueous solubility and low cell penetration of the current hybrid compounds call for further structural optimization.

Keywords

Alantolactone; BRCA1/2 mutant; Olaparib; PARP1; Synthetic lethality.

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