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.

癌细胞依赖肌动蛋白细胞骨架重排来执行标志性的恶性功能，包括激活、增殖、迁移和侵袭。Wiskott-Aldrich 综合征蛋白 (WASp) 是一种肌动蛋白成核促进因子，是造血细胞中肌动蛋白聚合的关键调节因子。WASp 在恶性肿瘤中的参与尚不完全清楚。由于 WASp 仅在造血细胞中表达，因此我们在计算机上进行了筛选以识别结合 WASp 并促进其降解的小分子化合物 (SMC)。我们在这里描述了一种这样的鉴定分子；这种 WASp 靶向 SMC 在体外和体内抑制几种类型的造血系统恶性肿瘤中关键的 WASp 依赖性肌动蛋白过程，而不会影响幼稚的健康细胞。这种小分子表现出有限的毒性和免疫原性作用，因此可以作为一种以安全和精确靶向的方式治疗特定造血系统恶性肿瘤的有效策略。