Design and Development of PDI Inhibitors for Treatment of Glioblastoma

By May 26, 2020Articles

By Suhui Yang, Ph.D.
Associate Professor, Department of Pharmaceutical Sciences

Glioblastoma (GBM) is the most common and most aggressive type of primary human brain tumor. The standard of care for GBM is surgical resection followed by radiotherapy in combination with the DNA-alkylating agent temozolomide (TMZ). However, only 5.5 % of patients survive more than 5 years after diagnosis. The current treatments are effective at shrinking tumors initially, but they are not curative, and cancer ultimately recurs in almost all patients due to drug resistance and tumor heterogeneity. No successful drug treatment for GBM has been approved for over three decades. Therefore, there exists an urgent need for the development of novel and effective therapies for GMB.

A cell-stress response pathway, the unfolded protein response (UPR), has emerged as a promising target for the development of cancer treatments. This pathway is activated in response to a disturbance in endoplasmic reticulum (ER) homeostasis, and the failure of ER homeostasis leads to the initiation of cell apoptosis. Protein disulfide isomerase (PDI) is a dithiol-disulfide oxidoreductase with molecular chaperone functions. Mainly located in the ER, PDI mediates oxidative protein folding and is upregulated by the UPR as a cancer survival mechanism. So, PDI inhibition results in the accumulation of unfolded and misfolded proteins, ER stress, and cell death.

Dr. Yang has been involved in designing and developing novel small molecule compounds as potent and selective PDI inhibitors for the treatment of GBM [1-3]. A synthetic small-molecule compound, BAP2, was identified through a two-step phenotypic screening of 20,000 in-house chemical libraries, and BAPs were selected as a lead compound with lower IC50 of 930 nM against PDI. Unlike other PDI inhibitors targeting catalytic domains among thiol isomerases, BAP2 showed specific inhibition towards PDI over a panel of PDI family members. Also, BAP2 suppressed tumor growth in a mouse model as effective as TMZ, but without the toxicity associated with DNA alkylating agents. Also, BAP2 and its analogs inhibited cell migration by downregulating MMP9, one of the migration markers. The extensive transcriptomic and proteomic analysis demonstrated that the BAP2 and its analogs alter the transcription of genes involved in the UPR, ER stress, and apoptosis, and PDI inhibition downregulates DNA repair and DNA damage response genes. The molecular docking and mutation experiments indicated that BAP2 and its analogs bind to His256 in the allosteric hydrophobic site of PDI, ultimately causing conformational change to block the active site possibly due to displacement of the linker. These findings indicate that BAP2 compounds have anti-tumor activity and the suppressive effect on DNA repair gene expression warrants combination with DNA damaging agents to treat GBM.

  1. S. Xu, Y. Liu, K. Yang, H. Wang, A. Shergalis, A. Kyani, A. Bankhead, S. Tamura, S. Yang, X. Wang, C. Wang, A. Rehemtulla, M. Ljungman, N. Neamati, “Inhibition of protein disulfide isomerase in glioblastoma causes marked downregulation of DNA repair and DNA damage response genes”, Theranostics, (2019), 9, 2282.
  2. S. Yang, A. Shergalis, D. Lu, A. Kyani, Z. Lu, M. Ljungman, N. Neamati, “Design, Synthesis, and Biological Evaluation of Novel Allosteric Protein Disulfide Isomerase Inhibitors”, J. Med. Chem., (2019), 62, 3447.
  3. A. Kyani, S. Tamura, S. Yang (co-first), A. Shergalis, S. Samanta, Y. Kuang, M. Ljungman, N. Neamati, “Discovery and Mechanistic Elucidation of a Class of Protein Disulfide Isomerase Inhibitors for the Treatment of Glioblastoma”, Chem. Med. Chem., (2018), 13, 164.

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