A first-in-class Wiskott-Aldrich syndrome protein activator with anti-tumor activity in hematologic cancers.

Publication

A first-in-class Wiskott-Aldrich syndrome protein activator with anti-tumor activity in hematologic cancers.

Journal Paper/Review - Jun 20, 2024

Spriano Filippo, Sartori Giulio, Sgrignani Jacopo, Barnabei Laura, Arribas Alberto, Guala Matilde, Del Amor Ana Maria Carrasco, Tomasso Meagan R, Tarantelli Chiara, Cascione Luciano, Golino Gaetanina, Riveiro Maria E, Bortolozzi Roberta, Lupia Antonio, Paduano Francesco, Huguet Samuel, Rezai Keyvan, Rinaldi Andrea, Margheriti Francesco, Ventura-Aguiar Pedro, Guarda Greta, Costa Giosuè, Rocca Roberta, Furlan Alberto, Verdonk Luuk M, Innocenti Paolo, Martin Nathaniel I, Viola Giampietro, Driessen Christoph, Zucca Emanuele, Stathis Anastasios, Gahtory Digvijay, Van den Nieuwboer Maurits, Bornhauser Beat, Alcaro Stefano, Trapasso Francesco, Cristobal Susana, Padrick Shae B, Pazzi Natalina, Cavalli Franco, Cavalli Andrea, Gaudio Eugenio, Bertoni Francesco

Citation

Spriano F, Sartori G, Sgrignani J, Barnabei L, Arribas A, Guala M, Del Amor A, Tomasso M, Tarantelli C, Cascione L, Golino G, Riveiro M, Bortolozzi R, Lupia A, Paduano F, Huguet S, Rezai K, Rinaldi A, Margheriti F, Ventura-Aguiar P, Guarda G, Costa G, Rocca R, Furlan A, Verdonk L, Innocenti P, Martin N, Viola G, Driessen C, Zucca E, Stathis A, Gahtory D, Van den Nieuwboer M, Bornhauser B, Alcaro S, Trapasso F, Cristobal S, Padrick S, Pazzi N, Cavalli F, Cavalli A, Gaudio E, Bertoni F. A first-in-class Wiskott-Aldrich syndrome protein activator with anti-tumor activity in hematologic cancers. Haematologica 2024

Type

Journal Paper/Review (English)

Journal

Haematologica 2024

Publication Date

Jun 20, 2024

Issn Electronic

1592-8721

Brief description/objective

Hematological cancers are among the most common cancers in adults and children. Despite significant improvements in therapies, many patients still succumb to the disease. Therefore, novel therapies are needed. The Wiskott-Aldrich syndrome protein (WASp) family regulates actin assembly in conjunction with the Arp2/3 complex, a ubiquitous nucleation factor. WASp is expressed exclusively in hematopoietic cells and exists in two allosteric conformations: autoinhibited or activated. Here, we describe the development of EG-011, a first-in-class small molecule activator of the WASp auto-inhibited form. EG-011 possesses in vitro and in vivo anti-tumor activity as a single agent in lymphoma, leukemia, and multiple myeloma, including models of secondary resistance to PI3K, BTK, and proteasome inhibitors. The in vitro activity was confirmed in a lymphoma xenograft. Actin polymerization and WASp binding was demonstrated using multiple techniques. Transcriptome analysis highlighted homology with drugs-inducing actin polymerization.