SUMO Modification and Cancer Therapy

许多催化泛素样（Ubl）修饰的酶已被鉴定为靶点， 对危及生命但无法治愈的人类疾病的治疗进展。然而，Ubl FDA批准的药物对修饰的处理很差，突出了巨大的潜力， 利用这种类型的翻译后修饰来解决未满足的医疗需求。 Ubl与靶蛋白的缀合通过激活Ubl的C末端开始，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SUMO激活酶（SAE），已被验证为治疗靶点， 动物模型和早期临床研究。我们最近发现了一种保守的 SAE上的隐蔽位点提供了一种范式转换的变构方法来抑制Ubl 活化酶在下一个拨款期内，我们会进一步阐明 构效关系。此外，我们将验证变构抑制 我们发现的一种方法可以降低针对Ubl激活的癌症耐药性。 内切酶此外，我们将定义SUMO化的分子机制， 调节I型IFN的表达，并证实SAE抑制是一种有效的方法， 诱导免疫性冷结直肠癌抗肿瘤免疫。拟议的研究建立 我们在上一个资助周期的科学进展和我们20多年来的 研究SUMO化的经验。预计拟议的研究将产生长期的- 持久的影响，将刺激创新，针对Ubl的治疗开发， 导致新的免疫治疗策略的免疫冷肿瘤，不响应 目前的免疫疗法和高度未满足的需求，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.