Multiple myeloma (MM) is an incurable hematological cancer characterized by MM cells accumulation in the bone marrow (BM) that promotes tumor survival and drug resistance. The oncogenic Notch signaling consists of 4 receptors (Notch1-4) and 5 ligands (Jag1,2 and Dll1,3,4) and plays a crucial role in MM. In particular, aberrant Notch2 activation and Jag1 and 2 overexpression stimulate MM cells to establish pathological interactions with BM that trigger MM progression (1). These effects can be interfered by knocking down of Jag1 and 2 expression (2). This evidence prompts us to develop a therapeutic tool to selectively inhibit Notch2 signaling triggered by Jag1/2. We applied in silico protein-protein docking and virtual high-throughput screening (HTS) of a chemoteque to select druglike small molecules. The biological activity was validated by a Notch responsive reporter assay and co-culture assay that allows to measure Notch2 transcriptional activity induced either by Jag or Dll ligands. Based on previous setup integrated in silico pipeline (3), we applied a strategy to exclusively uncouple Notch2-Jag1/2, leaving unaltered the interaction with Dll that allows to overcome a gut toxicity causing by Notch pan-inhibitors. 100 top-scoring compounds directed exclusively to Notch2-Jag2 surface were selected by HTS of the chemoteque. 2 of 100 compounds validated in vitro significantly reduced Notch activity in the reporter assay on HEK293T cells. The co-culture assay of Hela cells overexpressing Notch2 with NIH3T3 overexpressing Jag1 or Dll4 ligands identified one promising compound that specifically inhibited Notch2-Jag1 and not Notch2-Dll4 interactions. We have identified compounds that selectively antagonize Notch activation. This lays a basis for an effective and safe Notch-directed anti-tumor therapy in MM and other Notch-dependent tumors. 1.Houde C, et al. Blood. 2004;104:3697-704 2.Colombo M, et al. Oncotarget. 2014;5:10393-406 3. Platonova N, et al. PlosOne. 2017, in print.
A new strategy for selective NOTCH2 targeting in multiple myeloma based on small molecules hampering receptor-ligand interaction / N. Platonova, C. Parravicini, L. Palazzolo, S. Saporiti, M. Colombo, V. Vallelonga, R. Colella, F. Baccianti, A. Neri, I. Eberini, R. Chiaramonte - In: International workshop From Cancerogenesis to Therapy: new paradigms, new opportunitiesPrima edizione. - [s.l] : University of Piemonte Orientale, 2017 Oct 30. - pp. 127-127 (( convegno International workshop NO-CANCER 2017 tenutosi a Novara nel 2017.
|Titolo:||A new strategy for selective NOTCH2 targeting in multiple myeloma based on small molecules hampering receptor-ligand interaction|
|Settore Scientifico Disciplinare:||Settore MED/04 - Patologia Generale|
Settore BIO/13 - Biologia Applicata
|Data di pubblicazione:||30-ott-2017|
|Tipologia:||Book Part (author)|
|Appare nelle tipologie:||03 - Contributo in volume|