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：
10908041
负责人：
Hong-Yu Li
金额：
$ 65.8万
依托单位：
UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
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 2028-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10908041
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 F-box 蛋白，构成 SCF 泛素 E3 连接酶复合物的四个亚基之一，调节通过靶向其底物（例如细胞周期抑制剂）的泛素化和降解来促进细胞周期进展第 27 页。 Skp2 E3 连接酶在癌症中具有广泛的意义，特别是对于不依赖雄激素的人类转移性癌症前列腺癌。我们发现转移性前列腺癌标本中 Skp2 表达上调和去势抵抗性前列腺癌（CRPC）并与 Myc 表达相关。我们进一步证明了 Skp2 是 Akt 的一种新型 E3 连接酶，可触发 Akt 的非蛋白水解 K63 连接泛素化，从而促进生长因子介导的 Akt 膜募集和激活。所有人一起建议 Skp2 同时调节 Akt 信号传导和 p27 降解，以及 TWIST 介导的 EMT 以促进 CRPC 进展和对雄激素剥夺疗法（ABT）的抵抗。尽管 Skp2 SCF 复合物 E3 连接酶是经过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，癌症的药物靶点 E3 连接酶仍被认为是非药物性的。靶向嵌合体的蛋白水解（PROTAC）方法可以由于其催化降解而增加非药物抑制剂的效力。在这个提案中，我们发现一种有效的 Skp2 PRO-1，其体外治疗窗口比小分子抑制剂提高了 100 倍以上。 Skp2-PRO-1 可以在癌细胞中以 100 nM 浓度完全降解 Skp2，并证明在挑战性和晚期 CRPC 肿瘤中完成体内 Skp2 降解和强大的抗肿瘤功效模型包括具有完整免疫力的遗传性 CRPC 小鼠模型。为了获得两名临床候选人，我们将评估 Skp2-PRO-1（一种基于 Cereblon 的 PROTAC）的 PK 特性，并改善其 PK 和药物作为第一个临床候选者的特性。我们将进一步开发基于 VHL/或 MDM2 的 Skp2 PROTAC 作为后备候选人。最后，我们将使用先进的 CRPC 体内模型验证临床候选药物不同的异种移植模式、癌症类器官、患者来源的异种移植物 (PDX) 和遗传小鼠模型。这由此产生的临床候选者将进入 IND 阶段，从而能够进行 I 期临床试验的研究癌症的治疗。