Drug screens leading to successful targeted therapies in cancer have been mainly based on cell viability assays identifying inhibitors of dominantly acting oncogenes. In contrast, there has been little success in discovering targeted therapies that reverse the effects of inactivating mutations in tumor suppressor genes. BAP1 is one such tumor suppressor that is frequently inactivated in a variety of cancers, including uveal melanoma, renal cell carcinoma, and mesothelioma. Since BAP1 is an epigenetic transcriptional regulator of developmental genes, we designed a two-phase drug screen involving a cell-based rescue screen of transcriptional repression caused by BAP1 loss, followed by an in vivo screen of lead compounds for rescue of a BAP1-deficient phenotype with minimal toxicity in Xenopus embryos. The first screen identified 9 compounds, 8 of which were HDAC inhibitors. The second screen eliminated all except one compound due to inefficacy or toxicity. The resulting lead compound, quisinostat, has a distinctive activity spectrum, including high potency against HDAC4, which was recently shown to be a key target of BAP1. Quisinostat was further validated in a mouse model and found to prevent the growth of BAP1-mutant uveal melanomas. This innovative strategy demonstrates the potential for identifying therapeutic compounds that target tumor suppressor mutations in cancer. Implications: Few drugs have been identified that target mutations in tumor suppressors. Using a novel 2-step screening approach, strategy, we identified quisinostat as a candidate for therapy in BAP1-mutant uveal melanoma. HDAC4 is implicated as a key target in uveal melanoma and perhaps other BAP1-mutant cancers.

中文翻译：

---

功效和毒性双重筛选鉴定了具有独特活性谱的 HDAC 抑制剂，用于治疗 BAP1 突变葡萄膜黑色素瘤

导致癌症靶向治疗成功的药物筛选主要基于细胞活力测定，以确定主要作用的癌基因的抑制剂。相比之下，在发现逆转肿瘤抑制基因失活突变影响的靶向疗法方面几乎没有成功。BAP1 是一种这样的肿瘤抑制因子，在多种癌症中经常失活，包括葡萄膜黑色素瘤、肾细胞癌和间皮瘤。由于 BAP1 是发育基因的表观遗传转录调节因子，我们设计了一种两阶段药物筛选，包括基于细胞的 BAP1 缺失引起的转录抑制的拯救筛选，然后是用于拯救 BAP1 缺陷的先导化合物的体内筛选在非洲爪蟾胚胎中具有最小毒性的表型。第一个筛选确定了 9 种化合物，其中8种是HDAC抑制剂。由于无效或毒性，第二次筛选消除了除一种化合物之外的所有化合物。由此产生的先导化合物 quisinostat 具有独特的活性谱，包括对 HDAC4 的高效力，它最近被证明是 BAP1 的关键目标。Quisinostat 在小鼠模型中得到进一步验证，发现可以防止 BAP1 突变葡萄膜黑色素瘤的生长。这一创新策略证明了识别靶向癌症中肿瘤抑制突变的治疗化合物的潜力。启示：很少有药物可以靶向肿瘤抑制基因的突变。使用一种新的两步筛选方法、策略，我们将 quisinostat 确定为治疗 BAP1 突变葡萄膜黑色素瘤的候选药物。HDAC4 被认为是葡萄膜黑色素瘤和其他 BAP1 突变癌症的关键靶点。