Haematologica. 2024 Jun 20.
Filippo Spriano,
Giulio Sartori,
Jacopo Sgrignani,
Laura Barnabei,
Alberto J Arribas,
Matilde Guala,
Ana Maria Carrasco Del Amor,
Meagan R Tomasso,
Chiara Tarantelli,
Luciano Cascione,
Gaetanina Golino,
Maria E Riveiro,
Roberta Bortolozzi,
Antonio Lupia,
Francesco Paduano,
Samuel Huguet,
Keyvan Rezai,
Andrea Rinaldi,
Francesco Margheriti,
Pedro Ventura,
Greta Guarda,
Giosuè Costa,
Roberta Rocca,
Alberto Furlan,
Luuk M Verdonk,
Paolo Innocenti,
Nathaniel I Martin,
Giampietro Viola,
Christoph Driessen,
Emanuele Zucca,
Anastasios Stathis,
Digvijay Gahtory,
Maurits Van den Nieuwboer,
Beat Bornhauser,
Stefano Alcaro,
Francesco Trapasso,
Susana Cristobal,
Shae B Padrick,
Natalina Pazzi,
Franco Cavalli,
Andrea Cavalli,
Eugenio Gaudio,
Francesco Bertoni.
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.