Intrinsically disordered proteins (IDPs) are emerging as attractive drug targets by virtue of their prevalence in various diseases including cancer. Drug development targeting IDPs is challenging because IDPs have dynamic structure features and conventional drug design is not applicable. NUPR1 is an IDP that plays an important role in pancreatic cancer. We previously reported that trifluoperazine (TFP), an antipsychotic agent, was capable of binding to NUPR1 and inhibiting tumor growth. Unfortunately, TFP showed strong central nervous system side effects. In the present work, we undertook a multidisciplinary approach to optimize TFP based on the synergy of computer modeling, chemical synthesis, and a variety of biophysical, biochemical, and biological evaluations. A family of TFP-derived compounds was produced and the most active one, ZZW-115, showed a dose-dependent tumor regression with no neurological effects and an ability to induce cell death mainly by necroptosis. This study opens a new perspective for drug development against IDPs, demonstrating the possibility of successful ligand-based drug design for such challenging targets.
Patricia Santofimia-Castaño, Yi Xia, Wenjun Lan, Zhengwei Zhou, Can Huang, Ling Peng, Philippe Soubeyran, Adrián Velázquez-Campoy, Olga Abián, Bruno Rizzuti, José L. Neira, Juan Iovanna
Guidelines: The Editorial Board will only consider letters that we deem relevant and of interest to our readers. We will not post data that have not been subjected to peer review, nor will we post letters that are essentially a reiteration of another letter. We reserve the right to edit any letter for length, content, and clarity. Authors will be notified by e-mail if their letters were accepted. No appeals will be considered.
Specific requirements: All letters must be 400 words or fewer. You may enter the letter as plain text or HTML. The author's name and e-mail address are required, and will be posted with the letter. All possible conflicts of interest must be noted, even if they are not posted. If you wish to include a figure (keep in mind that non-peer-reviewed data will not be posted), please contact the editors directly at email@example.com.