Increasing evidence suggests the pivotal role of hematopoietic pre-B-cell leukemia transcription factor (PBX)-interacting protein (HPIP/PBXIP1) in cancer development and progression, indicating that HPIP inhibition may be a promising target for cancer therapy. Here, we screened compounds inhibiting breast cancer cell proliferation with HPIP fused with green fluorescent protein as a reporter. A novel agent named TXX-1-10 derived from rimonabant, an antagonist of cannabinoid receptor 1 with anticancer effects, has been discovered to reduce HPIP expression and has greater inhibitory effects on breast cancer cell growth and metastasis in vitro and in vivo than rimonabant. TXX-1-10 regulates HPIP downstream targets, including several important kinases involved in cancer development and progression (e.g., AKT, ERK1/2, and FAK) as well as cell cycle-, apoptosis-, migration-, and epithelial-to-mesenchymal transition (EMT)-related genes. Consistent with the results of anticancer effects, genome-wide RNA sequencing indicated that TXX-1-10 has more significant effects on regulation of the expression of genes related to DNA replication, cell cycle, apoptosis, cell adhesion, cell migration, and invasion than rimonabant. In addition, TXX-1-10 significantly regulated genes associated with the cell growth and extracellular matrix organization, many of which were shown to be regulated by HPIP. Moreover, compared with rimonabant, TXX-1-10 greatly reduces blood-brain barrier penetrability to avoid adverse central depressive effects. These findings suggest that HPIP inhibition may be a useful strategy for cancer treatment and TXX-1-10 is a promising candidate drug for cancer therapy.

越来越多的证据表明造血前 B 细胞白血病转录因子 (PBX) 相互作用蛋白 (HPIP/PBXIP1) 在癌症发展和进展中的关键作用，表明 HPIP 抑制可能是癌症治疗的一个有希望的目标。在这里，我们用 HPIP 与绿色荧光蛋白融合作为报告基因筛选了抑制乳腺癌细胞增殖的化合物。一种名为 TXX-1-10 的新型药物源自利莫那班，一种具有抗癌作用的大麻素受体 1 拮抗剂，已被发现可降低 HPIP 表达，并且在体外和体内对乳腺癌细胞的生长和转移具有比利莫那班更大的抑制作用。TXX-1-10 调节 HPIP 下游靶标，包括参与癌症发展和进展的几种重要激酶（例如，AKT、ERK1/2 和 FAK）以及细胞周期-、细胞凋亡、迁移和上皮间质转化 (EMT) 相关基因。与抗癌作用的结果一致，全基因组RNA测序表明TXX-1-10对DNA复制、细胞周期、细胞凋亡、细胞粘附、细胞迁移和侵袭相关基因表达的调控作用比TXX-1-10更显着。利莫那班。此外，TXX-1-10 显着调节与细胞生长和细胞外基质组织相关的基因，其中许多被证明受 HPIP 调节。此外，与利莫那班相比，TXX-1-10 大大降低了血脑屏障的渗透性，以避免不利的中枢抑制作用。这些发现表明，HPIP 抑制可能是一种有用的癌症治疗策略，TXX-1-10 是一种很有前景的癌症治疗候选药物。和上皮间质转化 (EMT) 相关基因。与抗癌作用的结果一致，全基因组RNA测序表明TXX-1-10对DNA复制、细胞周期、细胞凋亡、细胞粘附、细胞迁移和侵袭相关基因表达的调控作用比TXX-1-10更显着。利莫那班。此外，TXX-1-10 显着调节与细胞生长和细胞外基质组织相关的基因，其中许多被证明受 HPIP 调节。此外，与利莫那班相比，TXX-1-10 大大降低了血脑屏障的渗透性，以避免不利的中枢抑制作用。这些发现表明，HPIP 抑制可能是一种有用的癌症治疗策略，TXX-1-10 是一种很有前景的癌症治疗候选药物。和上皮间质转化 (EMT) 相关基因。与抗癌作用的结果一致，全基因组RNA测序表明TXX-1-10对DNA复制、细胞周期、细胞凋亡、细胞粘附、细胞迁移和侵袭相关基因表达的调控作用比TXX-1-10更显着。利莫那班。此外，TXX-1-10 显着调节与细胞生长和细胞外基质组织相关的基因，其中许多被证明受 HPIP 调节。此外，与利莫那班相比，TXX-1-10 大大降低了血脑屏障的渗透性，以避免不利的中枢抑制作用。这些发现表明，HPIP 抑制可能是一种有用的癌症治疗策略，TXX-1-10 是一种很有前景的癌症治疗候选药物。