Preclinical Evaluation of Bavdegalutamide (ARV-110), a Novel PROteolysis TArgeting Chimera Androgen Receptor Degrader.

IF 5.3 2区 医学 Q1 ONCOLOGY
Lawrence B Snyder, Taavi K Neklesa, Ryan R Willard, Deborah A Gordon, Jennifer Pizzano, Nicholas Vitale, Kaitlynn Robling, Madeline A Dorso, Walid Moghrabi, Sean Landrette, Richard Gedrich, Sang Hyun Lee, Ian C A Taylor, John G Houston
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Abstract

Androgen receptor (AR) signaling is the principal driver of prostate cancer, and drugs that target this pathway (e.g., abiraterone and enzalutamide) are standard treatments for metastatic hormone-sensitive prostate cancer and metastatic castration-resistant prostate cancer (mCRPC). However, continual evolution during prostate cancer progression can result in AR alterations (e.g., mutation, amplification, splicing) that can cause tumors to become resistant to these therapies. Bavdegalutamide (ARV-110) is a PROteolysis TArgeting Chimera (PROTAC®) protein degrader that recruits the cereblon-containing E3 ubiquitin ligase to direct the polyubiquitination and subsequent proteasomal degradation of AR. Bavdegalutamide selectively degrades wild-type AR and most clinically relevant mutants with low nanomolar potency. The superiority of the degradation mechanism of action is demonstrated by bavdegalutamide's higher activity relative to the AR antagonist enzalutamide in cell-based systems that assess effects on prostate-specific antigen (PSA) synthesis, prostate cancer cell proliferation, and induction of apoptosis. In an AR-expressing patient-derived xenograft mouse model, bavdegalutamide showed substantial AR degradation and greater tumor growth inhibition compared with enzalutamide. Bavdegalutamide also showed robust tumor growth inhibition in enzalutamide- and abiraterone-resistant prostate cancer animal models and enhanced activity in combination with abiraterone. These promising preclinical data supported clinical development of bavdegalutamide as a potential treatment for patients with prostate cancer. Bavdegalutamide was the first PROTAC protein degrader to enter human clinical trials, specifically in patients with mCRPC in a phase 1/2 study (NCT03888612).

雄激素受体(AR)信号转导是前列腺癌的主要驱动因素,靶向这一通路的药物(如阿比特龙和恩杂鲁胺)是治疗转移性激素敏感性前列腺癌和转移性阉割耐药前列腺癌(mCRPC)的标准疗法。然而,前列腺癌发展过程中的持续演变会导致AR发生改变(如突变、扩增、剪接),从而导致肿瘤对这些疗法产生耐药性。Bavdegalutamide(ARV-110)是一种PROteolysis TArgeting Chimera (PROTAC®)蛋白降解剂,它能招募含有脑隆的E3泛素连接酶,引导AR的多泛素化和随后的蛋白酶体降解。巴夫地加鲁胺能选择性地降解野生型AR和大多数临床相关突变体,药效低至纳摩尔。在评估对前列腺特异性抗原(PSA)合成、前列腺癌细胞增殖和诱导细胞凋亡的影响的细胞系统中,巴夫地加鲁胺的活性高于AR拮抗剂恩杂鲁胺,这证明了降解作用机制的优越性。在表达 AR 的患者异种移植小鼠模型中,与恩扎鲁胺相比,巴夫地加鲁胺显示出大量的 AR 降解和更强的肿瘤生长抑制作用。在恩扎鲁胺和阿比特龙耐药的前列腺癌动物模型中,巴夫地加鲁胺也显示出强大的肿瘤生长抑制作用,与阿比特龙联用时活性更强。这些前景看好的临床前数据支持了巴夫地加鲁胺作为前列腺癌患者潜在治疗药物的临床开发。巴夫地加鲁胺是第一个进入人体临床试验的PROTAC蛋白降解剂,特别是在一项1/2期研究(NCT03888612)中用于mCRPC患者。
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来源期刊
CiteScore
11.20
自引率
1.80%
发文量
331
审稿时长
3 months
期刊介绍: Molecular Cancer Therapeutics will focus on basic research that has implications for cancer therapeutics in the following areas: Experimental Cancer Therapeutics, Identification of Molecular Targets, Targets for Chemoprevention, New Models, Cancer Chemistry and Drug Discovery, Molecular and Cellular Pharmacology, Molecular Classification of Tumors, and Bioinformatics and Computational Molecular Biology. The journal provides a publication forum for these emerging disciplines that is focused specifically on cancer research. Papers are stringently reviewed and only those that report results of novel, timely, and significant research and meet high standards of scientific merit will be accepted for publication.
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