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Abstract：
Despite the amenability of early-stage prostate cancer to surgery and radiation therapy, locally advanced and metastatic prostate cancer is clinically problematic. Chemical castration is often used as a first-line therapy for advanced disease, but progression to the castration-resistant prostate cancer phase occurs with dependable frequency, largely through mutations to the androgen receptor (AR), aberrant AR signaling, and AR-independent mechanisms, among other causes. Semaphorin 3C (SEMA3C) is a secreted signaling protein that is essential for cardiac and neuronal development and has been shown to be regulated by the AR, to drive epithelial-to-mesenchymal transition and stem features in prostate cells, to activate receptor tyrosine kinases, and to promote cancer progression. Given that SEMA3C is linked to several key aspects of prostate cancer progression, we set out to explore SEMA3C inhibition by small molecules as a prospective cancer therapy. A homology-based SEMA3C protein structure was created, and its interaction with the neuropilin (NRP)-1 receptor was modeled to guide the development of the corresponding disrupting compounds. Experimental screening of 146 in silico‒identified molecules from the National Cancer Institute library led to the discovery of four promising candidates that effectively bind to SEMA3C, inhibit its association with NRP1, and attenuate prostate cancer growth. These findings provide proof of concept for the feasibility of inhibiting SEMA3C with small molecules as a therapeutic approach for prostate cancer.
摘要：
尽管早期前列腺癌对手术和放射治疗有不利影响，局部晚期和转移性前列腺癌在临床上存在问题.化学去势常被用作晚期疾病的一线治疗,但是进展到去势抵抗前列腺癌阶段的频率可靠，主要通过雄激素受体（AR）的突变，异常AR信号，和AR独立机制，在其他原因中。信号素3C（SEMA3C）是一种分泌的信号蛋白，对心脏和神经元发育至关重要，并已被证明受AR调节，驱动前列腺细胞的上皮-间质转化和干细胞特征，激活受体酪氨酸激酶，并促进癌症进展。鉴于SEMA3C与前列腺癌进展的几个关键方面有关，我们着手探索小分子抑制SEMA3C作为一种前瞻性癌症治疗方法.创建了基于同源性的SEMA3C蛋白结构，并对其与神经纤毛素（NRP）-1受体的相互作用进行建模，以指导相应破坏化合物的开发。对来自美国国家癌症研究所图书馆的146个分子进行的实验筛选，导致发现了四种有效结合SEMA3C的有希望的候选物，抑制其与NRP1的关联，并减弱前列腺癌的生长。这些发现为用小分子抑制SEMA3C作为前列腺癌的治疗方法的可行性提供了概念证据。
