A first-in-class Wiskott-Aldrich syndrome protein (WASp) activator with anti-tumor activity in hematological cancers

Hematological cancers are among the most common cancers in adults and in 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 proteins regulate 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, auto-inhibited and active conformations. 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 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 induced by EG-011 was demonstrated with multiple techniques. Transcriptome analysis highlighted homology with drugs inducing actin polymerization. ### Competing Interest Statement The Foundation for the Institute of Oncology Research is the owner of the patent WO2019185117 on EG-011, in which Matilde Guala, Natalina Pazzi, Francesco Bertoni, Eugenio Gaudio are listed as co-inventors. Anastasios Stathis: institutional research funds from Pfizer, MSD; Roche, Novartis, Amgen, Abbvie, Bayer, ADC Therapeutics, MEI Therapeutics, Philogen, Celestia. Astra Zeneca; travel grant from AbbVie and PharmaMar; consulting fee payed to institution from Jansen, Roche, Eli Lilly. Emanuele Zucca: institutional research funds from Celgene, Roche and Janssen; advisory board fees from Celgene, Roche, Mei Pharma, Astra Zeneca and Celltrion Healthcare; travel grants from Abbvie and Gilead; expert statements provided to Gilead, Bristol-Myers Squibb and MSD. Francesco Bertoni: institutional research funds from Acerta, ADC Therapeutics, Bayer AG, Cellestia, CTI Life Sciences, EMD Serono, Helsinn, ImmunoGen, Menarini Ricerche, NEOMED Therapeutics 1, Nordic Nanovector ASA, Oncology Therapeutic Development, Oncternal Therapeutics, PIQUR Therapeutics AG; consultancy fee from Helsinn, Menarini; expert statements provided to HTG; travel grants from Amgen, Astra Zeneca, Jazz Pharmaceuticals, PIQUR Therapeutics AG. Eugenio Gaudio: currently, employee of Helsinn Healthcare SA, Lugano, Switzerland. The other Authors have nothing to disclose.