The retinoblastoma gene (RB) was discovered as the first tumor-suppressor gene. It was subsequently shown to be inactivated in most malignant tumors, particularly at the protein level. Therefore, many activated oncogenes as well as inactivated tumor-suppressor genes inactivate the function of the RB protein. I hypothesized that most of the molecular-targeting agents against activated oncogenes may reactivate the function of RB, and proposed screening systems for agents up-regulating the expression of cyclin-dependent kinase inhibitors, such as p15, p27, and p21, which convert the phosphorylated inactive form of the RB protein to the unphosphorylated active form. I termed this screening as “RB-reactivator screening”. Using the screening systems for agents that up-regulate the expression of p15, p27, and p21, we discovered the novel MEK inhibitor trametinib, the novel RAF/MEK inhibitor CH5126766/RO5126766/VS-6766, and the histone deacetylase inhibitor YM753/OBP-801, respectively. Trametinib exerted remarkable effects in patients with advanced BRAF mutant melanoma, and was approved in the USA as the first-in-class MEK inhibitor (trade name: Mekinist) in 2013. The British Pharmacological Society selected trametinib as the Drug Discovery of the Year in 2013. The combination of trametinib and the BRAF inhibitor dabrafenib was approved for advanced BRAF mutant melanoma in the USA, EU, Japan, and many other countries. Additionally, the US Food and Drug Administration (FDA) granted Breakthrough Therapy Designation for the combination of trametinib and dabrafenib in the treatment of patients with advanced BRAF mutant non-small cell lung cancer in 2015, and this combination was subsequently approved in the EU, USA, and Japan. In 2018, this combination was also approved for locally advanced or metastatic BRAF V600-mutant anaplastic thyroid cancer in the USA after it had been granted Breakthrough Therapy Designation by the FDA.

I describe here the characterization of our original screening system, RB-reactivator screening, by which these three molecular-targeting agents that advanced into clinical trials were identified.

视网膜母细胞瘤基因（RB）被发现是第一个肿瘤抑制基因。随后显示它在大多数恶性肿瘤中被灭活，特别是在蛋白质水平上。因此，许多活化的癌基因以及失活的肿瘤抑制基因使RB蛋白的功能失活。我假设大多数针对活化癌基因的分子靶向剂可能会重新激活 RB 的功能，并提出了上调细胞周期蛋白依赖性激酶抑制剂（如 p15、p27 和 p21）表达的药物筛选系统，它们可以转化RB蛋白的磷酸化无活性形式变为未磷酸化的活性形式。我将这种筛选称为“RB-再激活剂筛选”。使用上调 p15、p27 和 p21 表达的药物筛选系统，我们分别发现了新型 MEK 抑制剂曲美替尼、新型 RAF/MEK 抑制剂 CH5126766/RO5126766/VS-6766 和组蛋白去乙酰化酶抑制剂 YM753/OBP-801。曲美替尼对晚期 BRAF 突变黑色素瘤患者疗效显着，2013 年在美国获批为一流的 MEK 抑制剂（商品名：Mekinist）。英国药理学会评选曲美替尼为年度药物发现奖2013. 曲美替尼联合BRAF抑制剂达拉非尼在美国、欧盟、日本等国家获批治疗晚期BRAF突变黑色素瘤。此外，美国食品药品监督管理局（FDA）于 2015 年授予曲美替尼和达拉非尼联合治疗晚期 BRAF 突变非小细胞肺癌患者的突破性治疗指定，这种组合随后在欧盟、美国和日本获得批准。2018年，该组合在获得FDA突破性疗法认定后，在美国也获批用于治疗局部晚期或转移性BRAF V600突变型甲状腺癌。

我在这里描述了我们最初的筛选系统 RB 再激活剂筛选的特征，通过该系统确定了这三种进入临床试验的分子靶向剂。