编辑丨王多鱼

排版丨水成文

据世界卫生组织国际癌症研究机构

（IARC）发布的2020年全球癌症负担数据，2020年全球

全球新发癌症病例1929万例，其中男性1006万例，女性923万例。其中，乳腺癌新发病例高达226万例，超过了肺癌的220万例，成为全球第一大癌。除了乳腺癌之外，宫颈癌、子宫内膜癌和卵巢癌等妇科癌症同样

严重威胁着女性的健康和整体生活质量。

近日，生成式人工智能

（AI）驱动的临床阶段药物研发公司英矽智能

（Insilico Medicine）在

药物化学领域Top期刊 Journal of Medicinal Chemistry 期刊发表了一篇题为：

Discovery of Tetrahydropyrazolopyrazine Derivatives as Potent and Selective MYT1 Inhibitors for the Treatment of Cancer 的研究论文。

在英矽智能人工智能驱动的生成生物学和生成化学平台支持下，该研究发现了

MYT1作为乳腺癌和妇科癌症的治疗靶点的潜力，并设计了一系列靶向MYT1的新型、强效、高选择性抑制剂。

在全球范围内，乳腺癌

和妇科癌症严重威胁着女性的健康和整体生活质量。为了确定新疗法的潜在靶点，生成式人工智能

（AI）

驱动的临床阶段药物研发公司英矽智能

（Insilico Medicine）

的研究团队利用专有的由人工智能驱动的靶点识别平台PandaOmics

，分析了五种妇科癌症的数据，包括卵巢癌、子宫内膜癌、宫颈癌、乳腺癌，以及三阴性乳腺癌。值得注意的是，在所有疾病中，MYT1靶点和这些疾病的相关性始终位居前列。

MYT1是Wee1-激酶家族的成员，该蛋白在大多数正常组织中很少表达，但在多种癌症中高度表达。研究发现，MYT1抑制和CCNE1扩增构成合成致死效应，在细胞周期调控中发挥关键作用。这表明抑制MYT1是一种具有前景的、治疗CCNE1扩增肿瘤的药物开发策略。

然而，MYT1与Wee1高度同源，这使得设计高选择性的MYT1抑制剂充满挑战性。在本研究中，英矽智能在人工智能驱动的小分子生成平台Chemsitry42的支持下克服了这个难点。英矽智能利用Chemistry42基于结构的药物设计

（SBDD）策略，并设置严格的相似性和选择性筛选指标，从头开始设计了一系列靶向MYT1的化合物。在这些结构新颖的化合物中，有一个系列脱颖而出被选为苗头化合物。

英矽智能随后对该复合物进行了X射线晶体结构分析，发现细微的化学结构改变对化合物活性有重大影响。这些发现为进一步分子优化提供了指导，并帮助研究者发现了先导化合物。该分子具有良好的MYT1活性，对Wee1和其他激酶具有出色的选择性，从而降低了脱靶效应的潜在风险，使得化合物更为安全。在临床前研究中，该化合物还显示出理想的体内抗肿瘤功效，和具有开发潜力的ADME和PK/PD性质。

MYT1项目的研究流程

论文第一作者、英矽智能MYT1项目药物化学负责人王亚洲博士表示，

这个项目的创新方法不仅提供了一种有效的靶点识别策略，还发现了一种具有开发潜力的高选择性 MYT1 抑制剂。这个发现既拓展了公司的合成致死管线，也为寻找一种惠及患者的更安全、更有效的治疗策略提供了新思路。

论文链接

：

https://pubs.acs.org/doi/10.1021/acs.jmedchem.3c01476

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