Drug Development of Skp2 PROTACs in Cancer

Skp2 PROTAC 治疗癌症的药物开发

基本信息

批准号：
10578303
负责人：
Hong-Yu Li
金额：
--
依托单位：
UNIV OF ARKANSAS FOR MED SCIS
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-05-31 至 2023-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10578303
关键词：
Androgens BCL2 gene Back Binding Biological Assay Biological Availability Cancer Patient Cell Cycle Cell Cycle Progression Cells Complex Data Development Dose Drug Kinetics Drug Targeting Excretory function Failure Funding Genetic Growth Factor Human Immunity In Vitro Intravenous Link Liver Microsomes MDM2 gene Malignant Neoplasms Malignant neoplasm of prostate Marketing Mediating Membrane Metabolism Metastatic Prostate Cancer Modeling Mus Normal Cell Oral Organoids Paper Pharmaceutical Preparations Phase I Clinical Trials Phenotype Plasma Process Property Protac Proteins Resistance Safety Signal Transduction Skp2 Proteins Specimen Testing Therapeutic Ubiquitination Xenograft Model Xenograft procedure absorption analog androgen deprivation therapy cancer cell cancer therapy castration resistant prostate cancer cell killing chemical synthesis chimera drug clinical candidate cytotoxicity design drug candidate drug development improved in vitro Assay in vivo in vivo Model inhibitor meter mouse model novel patient derived xenograft model pharmacologic phase 1 study prostate cancer model prostate cancer progression protein protein interaction recruit scale up small molecule inhibitor tumor ubiquitin-protein ligase

项目摘要

Abstract Skp2, an F-box protein that constitutes one of the four subunits of the SCF ubiquitin E3 ligase complex, regulates cell-cycle progression by targeting ubiquitination and degradation of its substrates, such as the cell-cycle inhibitor p27. Skp2 E3 ligase has a broad implication in cancer, especially for androgen-independent human metastatic prostate cancer. We showed that Skp2 expression was upregulated in metastatic prostate cancer specimens and castration-resistant prostate cancer (CRPC) and correlated with Myc expression. We further demonstrated that Skp2 is a novel E3 ligase for Akt that triggers nonproteolytic K63-linked ubiquitination of Akt, facilitating growth factor-mediated Akt membrane recruitment and activation. All together suggest that Skp2 simultaneously regulates Akt signaling and p27 degradation, and TWIST-mediated EMT to promote CRPC progression and resistance to androgen deprivation therapy (ABT). Although Skp2 SCF complex E3 ligase is a highly validated drug target for cancer, due to the lack of an effective protein-protein interaction inhibitors, Skp2 SCF complex E3 ligase is still considered as non-drugable. The proteolysis targeting chimera (PROTAC) approach could increase potency of non-drugable inhibitors due to its catalytic degradation. In this proposal, we have discovered a potent Skp2 PRO-1 by improving therapeutic window more than 100 fold in vitro over small molecule inhibitors. Skp2-PRO-1 can completely degrade Skp2 with 100 nM concentration in cancer cells and demonstrate the complete in vivo Skp2 degradation and robust antitumor efficacy in challenging and advanced CRPC tumor models including the genetic CRPC mouse model with intact immunity. To obtain two clinical candidates, we will evaluate the PK properties of Skp2-PRO-1, a Cereblon based PROTAC and improve its PK and drug properties as the first clincial candidate. We will further develop a VHL/or MDM2 based Skp2 PROTAC as the back-up candidate. Finally we will validate the clinical candidates in advanced CRPC in vivo models using diverse xenograft modes, cancer organoids, patient-derived xenografts (PDXs) and genetic mouse models. The resulted clinical candidates will be advanced into the IND enabling studies for the phase I clinical trials for the treatment of cancer.

抽象的 SKP2是一种构成SCF泛素E3连接酶复合物的四个亚基之一的F-box蛋白，调节通过靶向其底物的泛素化和降解，例如细胞周期抑制剂，细胞周期的进展 p27。 SKP2 E3连接酶对癌症具有广泛的影响，特别是对雄激素独立的人体转移前列腺癌。我们表明SKP2表达在转移性前列腺癌标本中上调和耐castration的前列腺癌（CRPC），与MYC表达相关。我们进一步证明了该SKP2是AKT的一种新型E3连接酶，可触发Akt的非蛋白水解K63连接的泛素化，促进生长因子介导的AKT膜募集和激活。一起表明SKP2同时调节AKT信号传导和p27降解，以及扭曲介导的EMT，以促进CRPC的进展和对雄激素剥夺疗法（ABT）的抗性。尽管SKP2 SCF复合物E3连接酶是高度验证的由于缺乏有效的蛋白质 - 蛋白质相互作用抑制剂，SKP2 SCF复合物缺乏癌症的药物靶标 E3连接酶仍然被认为是不可阻挡的。蛋白水解靶向嵌合体（Protac）方法可以由于其催化降解而增加了不可阻止的抑制剂的效力。在此提案中，我们发现了通过在小分子抑制剂上改善治疗窗口超过100倍，一种有效的SKP2 Pro-1。 SKP2-PRO-1可以在癌细胞中以100 nm浓度的浓度完全降解SKP2，并证明在具有挑战性和晚期CRPC肿瘤中完成体内SKP2降解和强大的抗肿瘤功效包括具有完整免疫力的遗传CRPC小鼠模型的模型。要获得两个临床候选者，我们将评估Skp2-Pro-1的PK特性，Skp2-Pro-1是一种基于少数的Protac，并改善其PK和药物属性是第一个clincial候选者。我们将进一步开发基于VHL/或MDM2的SKP2 Protac 备用候选人。最后，我们将使用高级CRPC中的临床候选体内模型验证临床候选者各种异种移植模式，癌症类器官，患者衍生的异种移植物（PDXS）和遗传小鼠模型。这最终的临床候选者将获得I阶段临床试验的IND支持研究癌症的治疗。