SUMO Modification and Cancer Therapy

许多催化类泛素(UbL)修饰的酶已被确定为 缺乏治愈方法的危及生命的人类疾病的治疗进展。然而，Ubl FDA批准的药物对修改的处理很差，突显了巨大的潜力 利用这种翻译后修饰来解决未得到满足的医疗需求。 UbL与靶蛋白的结合始于UbL的C-末端的激活，这是一个步骤 由通常称为活化酶或E1的酶催化。几种E1酶， 包括相扑激活酶(SAE)，已被证实为治疗靶点 动物模型和早期临床研究。我们最近发现了一种保守的 SAE上的隐蔽位置提供了一种范式转换变构方法来抑制UBL 激活酶。在下一个资助期，我们将进一步阐明 结构-活性关系。此外，我们将验证变构抑制 我们发现的靶向Ub1激活降低癌症耐药性的方法 酵素。此外，我们将定义SUMO化的分子机制 调节I型干扰素的表达，并验证抑制SAE是一种有效的方法 诱导免疫冷结直肠癌的抗肿瘤免疫。建议的研究建立 关于我们在上一个资助周期中的科学进步和我们20多年来的 研究琥珀酰化反应的经验。拟议的研究预计将产生长期的- 持久的影响，将刺激创新，针对Ubl进行治疗开发和 导致对免疫感冒肿瘤无反应的新的免疫治疗策略 目前的免疫疗法和高度未得到满足的需求，如结直肠癌。

Many enzymes catalyzing ubiquitin-like (Ubl) modifications have been identified as targets for the therapeutic development of life-threatening human diseases that lack a cure. However, Ubl modifications are poorly addressed by FDA approved drugs, highlighting the immense potential to exploit this type of post-translational modification to address unmet medical needs. Conjugation of Ubls to target proteins begins by activation of the C-terminus of a Ubl, a step catalyzed by enzymes generally known as activating enzyme or E1. Several E1 enzymes, including the SUMO-activating enzyme (SAE), have been validated as therapeutic targets by animal models and by early phase clinical studies. Our recent discovery of a conserved cryptic site on the SAE provides a paradigm-shifting allosteric approach to inhibit Ubl activating enzymes. In the next funding period, we will further elucidate the mechanism of the structure-activity relationship. Additionally, we will validate that the allosteric inhibition approach we discovered reduces cancer drug resistance for targeting Ubl activating enzymes. Furthermore, we will define the molecular mechanism of how SUMOylation regulates type I IFN expression and validate that SAE inhibition is an effective approach to induce anti-tumor immunity for immune cold colorectal cancers. The proposed studies build on our scientific progress in the previous funding cycle and our more than 20-year experience in studying SUMOylation. The proposed studies are expected to result in long- lasting impacts that will spur innovation in targeting Ubl for therapeutic development and result in new immune therapeutic strategies for immune cold tumors that do not respond to current immune therapies and are high unmet needs, such as colorectal cancers.