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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.

摘要 Skp 2是一种F-box蛋白，它构成SCF泛素E3连接酶复合物的四个亚基之一，通过靶向泛素化和降解其底物（如细胞周期抑制剂）来调控细胞周期进程第27页。Skp 2 E3连接酶在癌症中具有广泛的意义，特别是对于雄激素非依赖性人类转移性肿瘤。前列腺癌我们发现Skp 2在转移性前列腺癌标本中表达上调，和去势抵抗性前列腺癌（CRPC），并与Myc表达相关。我们进一步表明 Skp 2是一种新型的Akt E3连接酶，可触发Akt的非蛋白水解K63连接的泛素化，生长因子介导的Akt膜募集和激活。所有这些都表明Skp 2同时调节Akt信号传导和p27降解，TWIST介导的EMT促进CRPC进展，雄激素剥夺疗法（ABT）。尽管Skp 2 SCF复合物E3连接酶是一种高度有效的针对肿瘤药物靶点，由于缺乏有效的蛋白质-蛋白质相互作用抑制剂，Skp 2 SCF复合物 E3连接酶仍然被认为是不可药用的。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药物化抑制剂效力。在这个提案中，我们发现一种有效的Skp 2 PRO-1，通过在体外将治疗窗口提高超过小分子抑制剂100倍。 Skp 2-PRO-1可以在癌细胞中以100 nM的浓度完全降解Skp 2，并证明了Skp 2-PRO-1在癌细胞中的作用。在挑战性和晚期CRPC肿瘤中完成体内Skp 2降解和稳健的抗肿瘤疗效包括具有完整免疫力的遗传CRPC小鼠模型。为了获得两个临床候选人，我们将评估Skp 2-PRO-1（一种基于Cereblon的PROTAC）的PK特性，并改善其PK和药物敏感性。作为第一临床候选人。我们将进一步开发基于VHL/或MDM 2的Skp 2 PROTAC，后备候选人最后，我们将在晚期CRPC体内模型中验证临床候选药物，不同的异种移植模型、癌症类器官、患者来源的异种移植物（PDX）和遗传小鼠模型。的最终的临床候选药物将进入IND使能研究，以进行I期临床试验，癌症的治疗。