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

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

The Mina and Everard Goodman Faculty of Life Sciences

Research output: Contribution to journal › Article › peer-review

2 Scopus citations

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.

Original language	English
Article number	5581
Pages (from-to)	5581
Journal	Nature Communications
Volume	12
Issue number	1
DOIs	https://doi.org/10.1038/s41467-021-25842-7
State	Published - 22 Sep 2021

Bibliographical note

Funding Information:
We thank Matan Y. Avivi, Anat Raiff, and Dr. Alex Vorvak for their technical assistance, Dr. Lisette Bronswijk-Deddens (Sartorius) for her help with the BLI data analysis and Prof. Bilha Fischer for her advice on the chemical characterization of the SMC. This research was funded in part by the Israel Science Foundation (grant no. 491/10), and in part by the Israel Innovation Authority.

Publisher Copyright:
© 2021, The Author(s).

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Biber, G., Ben-Shmuel, A., Noy, E., Joseph, N., Puthenveetil, A., Reiss, N., Levy, O., Lazar, I., Feiglin, A., Ofran, Y., Kedmi, M., Avigdor, A., Fried, S., & Barda-Saad, M. (2021). Targeting the actin nucleation promoting factor WASp provides a therapeutic approach for hematopoietic malignancies. Nature Communications, 12(1), 5581. [5581]. https://doi.org/10.1038/s41467-021-25842-7

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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 na{\"i}ve 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.",

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Biber, G, Ben-Shmuel, A, Noy, E, Joseph, N, Puthenveetil, A, Reiss, N, Levy, O, Lazar, I, Feiglin, A, Ofran, Y, Kedmi, M, Avigdor, A, Fried, S & Barda-Saad, M 2021, 'Targeting the actin nucleation promoting factor WASp provides a therapeutic approach for hematopoietic malignancies', Nature Communications, vol. 12, no. 1, 5581, pp. 5581. https://doi.org/10.1038/s41467-021-25842-7

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AU - Ben-Shmuel, Aviad

AU - Noy, Elad

AU - Joseph, Noah

AU - Puthenveetil, Abhishek

AU - Reiss, Neria

AU - Levy, Omer

AU - Lazar, Itay

AU - Feiglin, Ariel

AU - Ofran, Yanay

AU - Kedmi, Meirav

AU - Avigdor, Abraham

AU - Fried, Sophia

AU - Barda-Saad, Mira

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AB - 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.

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

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