Inducing Proximity: An Emerging Paradigm for New Therapeutic Modalities

诱导接近：新治疗方式的新兴范例

• 批准号: 10701073
• 负责人: CRAIG M CREWS
• 金额: $ 89.87万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-09 至 2029-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10701073
• 关键词: Academia; Address; Cell Culture Techniques; Clinical; Clinical Trials; Development; Disease; Drug Industry; Drug Targeting; Drug usage; FDA approved; Future; Genomics; Malignant neoplasm of prostate; Modality; Multiple Myeloma; Nuclear Hormone Receptors; Oncogenic; Oncology; Oncoproteins; Pharmaceutical Preparations; Pharmacologic Substance; Phase; Play; Proteasome Inhibitor; Proteins; Proteolysis; Refractory; Relapse; Research; Small Interfering RNA; Technology; Translating; Validation; Work; bench to bedside; drug candidate; drug development; first-in-human; in vivo; innovation; knock-down; malignant breast neoplasm; novel; novel anticancer drug; novel drug class; novel therapeutics; protein degradation; proteostasis; recruit; small molecule; success; translational cancer research; tumor; ubiquitin-protein ligase; wasting

The pharmaceutical industry is in a crisis; unfortunately the post-genomic era has not significantly changed the number of proteins pursued by drug companies. This dearth of new cancer drug targets has resulted in too many ‘me too’ drugs and wasted effort. To address this need, my lab has focused on developing the new field of ‘Controlled Proteostasis’. Our initial efforts focused on inhibiting protein turnover; we developed a novel proteasome inhibitor, YU101, which served as the basis of a new oncology-based biopharma, Proteolix, Inc. from my lab. Ultimately, YU101 became carfilzomib/Kyprolis®, which was approved by the FDA in 2012 for relapsed/refractory multiple myeloma. More recently, my lab has been focused on the flipside of protein turnover, i.e., developing a small molecule analogy to siRNA to induce protein knockdown. We have shown that this strategy, known as Proteolysis Targeting Chimerae (PROTACs) can effectively recruit targeted oncoproteins to E3 ubiquitin ligases for induced degradation, both in cell culture and in vivo. Over the past six years of the current R35, I have worked closely with another biopharma that I founded, Arvinas, Inc., to apply this approach to nuclear hormone receptors in oncology. Arvinas’ two PROTAC-based drug candidates (targeting AR and ER, for prostate and breast cancers, respectively) have been shown to decrease their target proteins in first-in-human clinical trials, thus validating our PROTAC technology. In the next R35 phase, I propose to develop this technology further through the identification of key degradable oncogenic driver proteins and through the development of tumor-selective PROTACs. Moreover, the clinical validation of PROTACs supports the development of additional novel therapeutic modalities based on heterobifunctional compounds that co-opt various intracellular machineries. These innovative approaches have the potential to be new drug development paradigms that could have a significant impact by dramatically expanding the protein classes one can target pharmaceutically. Finally, for the past 26 years, I have focused on translating research from my lab into both new oncology-focused ventures and a FDA-approved drug, thus demonstrating truly ‘bench-to- bedside’ research that is not common in academia today. This track record of innovation and execution within translational cancer research are strong predictors of continued future success.

制药行业正处于危机之中。不幸的是，基因组时代没有发生显着变化 制药公司追求的蛋白质数量。新的癌症药物靶标的死亡已导致 在太多的“我也是我”的毒品和浪费的努力中。为了满足这一需求，我的实验室专注于发展 “受控蛋白质的新领域”。我们的最初努力集中在抑制蛋白质更新。 开发了一种新型的蛋白酶体抑制剂YU101，它是新的基于肿瘤学的基础 Biopharma，Proteolix，Inc。来自我的实验室。最终，Yu101成为Carfilzomib/Kyprolis®， 2012年，FDA批准了复发/难治性多发性骨髓瘤。最近，我的实验室一直 专注于蛋白质周转的翻转，即产生与siRNA的小分子类比以诱导 蛋白质敲低。我们已经表明，该策略，称为靶向嵌合体的蛋白水解 （Protac）可以有效地募集靶向癌蛋白到E3泛素连接酶以诱导降解， 在细胞培养和体内。在当前R35的过去六年中，我与 我创建的另一种生物制药Arvinas，Inc。将这种方法应用于核马酮受体 肿瘤学。 Arvinas的两个基于Protac的药物候选者（针对AR和ER，用于前列腺和乳房 癌症分别已显示出在人类的第一个临床试验中降低其靶蛋白， 从而验证了我们的Protac技术。在下一个R35阶段，我建议开发这项技术 通过鉴定关键降解的致癌驱动蛋白以及通过开发 肿瘤选择性protac。此外，Protac的临床验证支持 基于异常化合物的其他新型热模态，可以选择各种 细胞内机器。这些创新的方法有可能成为新药开发 通过大大扩展蛋白质类，可以产生重大影响的范例 靶向药物。最后，在过去的26年中，我专注于翻译我的实验室的研究 进入新的以肿瘤学为重点的企业和FDA批准的药物，从而证明 床边的研究在今天的学术界并不常见。创新和执行的记录 在翻译癌症中，研究是持续未来成功的有力预测指标。

项目成果

Efficient Synthesis of Immunomodulatory Drug Analogues Enables Exploration of Structure-Degradation Relationships.

• DOI: 10.1002/cmdc.201800271
• 发表时间: 2018-08-10
• 期刊: ChemMedChem
• 影响因子: 3.4
• 作者: Burslem GM;Ottis P;Jaime-Figueroa S;Morgan A;Cromm PM;Toure M;Crews CM
• 通讯作者: Crews CM

MDM2-Recruiting PROTAC Offers Superior, Synergistic Antiproliferative Activity via Simultaneous Degradation of BRD4 and Stabilization of p53.

• DOI: 10.1158/0008-5472.can-18-2918
• 发表时间: 2019-01-01
• 期刊: Cancer research
• 影响因子: 11.2
• 作者: Hines J;Lartigue S;Dong H;Qian Y;Crews CM
• 通讯作者: Crews CM

Proteolysis targeting chimeras (PROTACs) come of age: entering the third decade of targeted protein degradation.

• DOI: 10.1039/d1cb00011j
• 发表时间: 2021-03-19
• 期刊: RSC chemical biology
• 影响因子: 4.1
• 作者: Bond MJ;Crews CM
• 通讯作者: Crews CM

Modulation of Phosphoprotein Activity by Phosphorylation Targeting Chimeras (PhosTACs).

• DOI: 10.1021/acschembio.1c00693
• 发表时间: 2021-12-17
• 期刊: ACS CHEMICAL BIOLOGY
• 影响因子: 4
• 作者: Chen, Po-Han;Hu, Zhenyi;An, Elvira;Okeke, Ifunanya;Zheng, Sijin;Luo, Xuanmeng;Gong, Angela;Jaime-Figueroa, Saul;Crews, Craig M.
• 通讯作者: Crews, Craig M.

PROTACs: An Emerging Therapeutic Modality in Precision Medicine.

• DOI: 10.1016/j.chembiol.2020.07.020
• 发表时间: 2020-08-20
• 期刊: CELL CHEMICAL BIOLOGY
• 影响因子: 8.6
• 作者: Nalawansha, Dhanusha A.;Crews, Craig M.
• 通讯作者: Crews, Craig M.