Development of SUMO1 small molecule degraders as the first-in-class anticancerdrugs for metastatic colorectal cancer

项目摘要/摘要 结直肠癌(CRC)是第四位确诊的癌症，但也是第二大癌症死亡原因。 由于其在肝脏和肺部的转移性疾病(MCRC)。目前还没有有效的治疗方法来治疗 诊断为结直肠癌的患者。该项目的最终目标是开发小分子的小分子降解剂 泛素相关修饰物1(SUMO1)作为治疗mCRC的一线抗癌药物。至 为了实现这一目标，我们已经确定了一种能够选择性降解癌症中的SUMO1蛋白的命中化合物 但不是正常细胞。围绕HIT化合物的构效关系(SAR)研究已经产生了我们的 具有改进的效力和类药物特性的先导化合物。使用基因定义的CRC细胞系，3- 三维(3D)有机物和患者来源的异种移植物(PDX)，我们已经证明了先导化合物 在治疗mCRC方面比目前的标准疗法更有效。我们早期的工作主要集中在 建立具有足够能力的连接良好的测试范例，包括所有所需的体外和体内测试 活体检测能够识别和表征当前的铅系列。在此SBIR第二阶段 项目，我们将优化我们的主导系列，目的是确定有效、选择性和口服生物利用度的SUMO1 降级候选人(S)。候选人(S)将具有必要的临床前疗效、安全性和药代动力学 预测它的特性能够充分探索mCRC患者的有效性和安全性。特别是，目标1 将利用我们的计算化学技术通过化学方法帮助设计新的化合物 铅系列的修改。每一种化合物都将经过合理的设计、合成和改进 我们已建立的化合物测试漏斗。首先，化合物将使用我们的大容量初级设备进行筛选， 二次筛选和反筛选分析它们的结合和靶标选择性。符合我们标准的化合物 将根据体外溶解性、渗透性、吸收、分布、代谢和排泄来选择成功的药物 对结直肠癌细胞系和3D有机化合物的抗癌活性进行评估和优先排序。在目标2中， 从AIM 1研究中选择的先导化合物将在#年进行药代动力学特性评估 啮齿动物以确定清除量和口服生物利用度。选定的化合物将进一步在体内进行评估 口服后使用我们的mCRC PDX模型的靶向参与度和治疗效果。成功 化合物将需要证明具有足够有效的体内剂量反应靶标参与 用于转换为可接受的预测人体治疗剂量和方案的剂量。优化的销售线索 通过AIM 2中的研究，将进一步评估化合物的毒理学、安全性、药理学、 AIM 3中狗的遗传毒性和口服生物利用度。本项目的里程碑是选择最佳的铅 进入临床前开发阶段的化合物(S)，研究性新药使能研究和 治疗被诊断为mCRC的患者的I期临床试验，mCRC是一种致命的人类疾病。

Project Summary/Abstract Colorectal carcinoma (CRC) is the 4th most diagnosed cancer but the 2nd leading cause of cancer death mainly due to its metastatic disease (mCRC) in the liver and lungs. Currently there is no effective therapy available for patients diagnosed with mCRC. The ultimate goal of this project is to develop small-molecule degraders of small ubiquitin-related modifier 1 (SUMO1) as the first-in-class anticancer drugs for treatment of mCRC therapy. To achieve this goal, we have already identified a hit compound that selectively degrades SUMO1 protein in cancer but not normal cells. Structure-activity relationship (SAR) studies around the hit compound have generated our lead compounds with improved potency and drug-like properties. Using genetically defined CRC cell lines, 3- dimensional (3D) organoids and patient’s derived xenografts (PDXs), we have shown that the lead compounds are more effective in treatment of mCRC than the current standard therapy. Our earlier work has focused on establishing a well-connected testing paradigm with sufficient capacity, including all the required in vitro and in vivo assays that has enabled identification and characterization of the current lead series. In this SBIR Phase II project, we will optimize our lead series with the aim to identify potent, selective and orally bioavailable SUMO1 degrader candidate(s). The candidate(s) will have the necessary preclinical efficacy, safety, and pharmacokinetic properties that predict it be enable full exploration of efficacy and safety in mCRC patients. In particular, Aim 1 will leverage our computational chemistry technology to assist the design of novel compounds through chemical modifications of the lead series. Each compound will be rationally designed, synthesized, and advanced through our established compound testing funnel. First, compounds will be screened using our high-capacity primary, secondary and counter-screen assays for their binding and target selectivity. Compounds that meet our criteria for success will be selected for in vitro solubility, permeability, absorption, distribution, metabolism, and excretion assessment and prioritized for the anticancer activity against CRC cell lines and 3D organoids. In Aim 2, the leading compounds selected from the studies of Aim 1 will be evaluated for their pharmacokinetic properties in rodents to determine clearance and oral bioavailability. Selected compound will be further assessed for in vivo target engagement and therapeutic efficacy using our mCRC PDX models after oral administration. Successful compounds will need to demonstrate an in vivo dose response target engagement with an adequate efficacious dose for translation into acceptable predicted human therapeutic dose and regimen. The optimized lead compounds through the studies in Aim 2 will be further evaluated for their toxicology, safety pharmacology, genotoxicity and oral bioavailability in dogs in Aim 3. The milestone of this project is to select the optimized lead compound(s) for advancement into preclinical development phase, investigative new drug-enabling studies and phase I clinical trials in treatment of patients diagnosed with mCRC, a deadly human disease.