Targeting the actin nucleation promoting factor WASp provides a therapeutic approach for hematopoietic malignancies

Guy Biber; Aviad Ben-Shmuel; Elad Noy; Noah Joseph; Abhishek Puthenveetil; Neria Reiss; Omer Levy; Itay Lazar; Ariel Feiglin; Yanay Ofran; Meirav Kedmi; Abraham Avigdor; Sophia Fried; Mira Barda-Saad

doi:10.1038/s41467-021-25842-7

Targeting the actin nucleation promoting factor WASp provides a therapeutic approach for hematopoietic malignancies

Nat Commun. 2021 Sep 22;12(1):5581. doi: 10.1038/s41467-021-25842-7.

Authors

Guy Biber^#¹, Aviad Ben-Shmuel^#¹, Elad Noy¹, Noah Joseph¹, Abhishek Puthenveetil¹, Neria Reiss¹, Omer Levy¹, Itay Lazar¹, Ariel Feiglin¹, Yanay Ofran¹, Meirav Kedmi^{1

2

3}, Abraham Avigdor^{2

3}, Sophia Fried¹, Mira Barda-Saad⁴

Affiliations

¹ The Mina and Everard Goodman Faculty of Life Sciences, Bar-Ilan University, Ramat-Gan, 5290002, Israel.
² Division of Hematology and Bone Marrow Transplantation, Chaim Sheba Medical Center, Tel Hashomer, Israel.
³ Sackler School of Medicine, Tel-Aviv University, Tel-Aviv, Israel.
⁴ The Mina and Everard Goodman Faculty of Life Sciences, Bar-Ilan University, Ramat-Gan, 5290002, Israel. [email protected].

^# Contributed equally.

Abstract

Cancer cells depend on actin cytoskeleton rearrangement to carry out hallmark malignant functions including activation, proliferation, migration and invasiveness. Wiskott-Aldrich Syndrome protein (WASp) is an actin nucleation-promoting factor and is a key regulator of actin polymerization in hematopoietic cells. The involvement of WASp in malignancies is incompletely understood. Since WASp is exclusively expressed in hematopoietic cells, we performed in silico screening to identify small molecule compounds (SMCs) that bind WASp and promote its degradation. We describe here one such identified molecule; this WASp-targeting SMC inhibits key WASp-dependent actin processes in several types of hematopoietic malignancies in vitro and in vivo without affecting naïve healthy cells. This small molecule demonstrates limited toxicity and immunogenic effects, and thus, might serve as an effective strategy to treat specific hematopoietic malignancies in a safe and precisely targeted manner.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Actins / metabolism
Animals
Antineoplastic Agents / metabolism*
Antineoplastic Agents / pharmacokinetics
Antineoplastic Agents / pharmacology
Antineoplastic Agents / therapeutic use*
Cell Movement / drug effects
Cell Proliferation / drug effects
Cytoskeletal Proteins / metabolism
Hematologic Neoplasms / drug therapy*
Hematologic Neoplasms / metabolism
Hematologic Neoplasms / pathology
Humans
Integrins / metabolism
Intracellular Signaling Peptides and Proteins / metabolism
Mice
Neoplasm Invasiveness
Protein Binding / drug effects
Small Molecule Libraries / metabolism
Small Molecule Libraries / pharmacokinetics
Small Molecule Libraries / pharmacology
Small Molecule Libraries / therapeutic use
Ubiquitination / drug effects
Wiskott-Aldrich Syndrome Protein / metabolism*
Xenograft Model Antitumor Assays

Substances

Actins
Antineoplastic Agents
Cytoskeletal Proteins
Integrins
Intracellular Signaling Peptides and Proteins
Small Molecule Libraries
WAS protein, human
WIPF1 protein, human
Wiskott-Aldrich Syndrome Protein