Abstract
Hematologic 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 autoinhibited form of WASp. EG-011 possesses in vitro and in vivo antitumor 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 were demonstrated using multiple techniques. Transcriptome analysis highlighted homology with drugs inducing actin polymerization.
MeSH terms
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Actins / metabolism
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Animals
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Antineoplastic Agents* / pharmacology
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Antineoplastic Agents* / therapeutic use
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Cell Line, Tumor
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Hematologic Neoplasms* / drug therapy
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Hematologic Neoplasms* / genetics
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Hematologic Neoplasms* / metabolism
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Hematologic Neoplasms* / pathology
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Humans
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Mice
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Wiskott-Aldrich Syndrome Protein* / genetics
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Wiskott-Aldrich Syndrome Protein* / metabolism
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Xenograft Model Antitumor Assays*
Substances
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Wiskott-Aldrich Syndrome Protein
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Antineoplastic Agents
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Actins
Grants and funding
Funding: This study was supported by funds from the Swiss National Science Foundation (31003A_163232/1) to FB; Eurostars Project E!2829 HEMATO-WASP to DG, MvdN and FB; Swiss National Science Foundation 310030_185185 to GGu; ERANET Marine Biotechnology project CYANOBESITY that it is co-financed by FORMAS, Sweden grant N. 2016-02004 (SC); the GOLIATH project that has received funding from the European Union’s Horizon 2020 research and innovation programme under grant agreement N. 825489 (to SC); IKERBASQUE, Basque Foundation for Science (to SC); Basque Government grant IT-971-16 (to SC) and LiU MS Core facility.