Abstract 494: BPI-452080: A potent and selective HIF-2α inhibitor for the treatment of clear cell renal cell carcinoma, von Hippel-Lindau disease, and other solid tumors

Abstract

The most observed alteration in clear cell renal cell carcinoma (ccRCC) is the inactivation of the tumor suppressor von Hippel-Lindau (VHL) E3 ligase due to genetic predisposition, somatic mutations, or methylation. Loss of VHL can lead to hypoxia-inducible factor 2α (HIF-2α) accumulation and elevated expression of HIF target genes, such as VEGFA, many of which facilitate angiogenesis, proliferation, and metastasis of ccRCC. Therefore, inhibiting HIF-2α has become a new strategy for the treatment of ccRCC. Here, we present the discovery of BPI-452080, a selective small molecule HIF-2α inhibitor. In VHL defective ccRCC cell lines, BPI-452080 potently and selectively blocked the heterodimerization of HIF-2α with HIF-1β, but not that of HIF-1α with HIF-1β. It inhibited the downstream hypoxia-responsive gene transcription and VEGFA protein secretion. In multiple xenograft mouse models, oral administration of BPI-452080 significantly inhibited tumor growth in a dose-dependent manner. BPI-452080 demonstrated good PK/PD correlation in the 786-O xenograft model after a single dosing, as shown by a concentration-dependent inhibition of VEGFA secretion in plasma and a reduction of the mRNA levels of VEGFA, CXCR4, CCND1, and GLUT1 genes in tumor tissue. Moreover, BPI-452080 exhibited good bioavailability in multiple pre-clinical species, favorable ADME properties, and good tolerance in toxicology studies. In conclusion, BPI-452080 is a potent, selective, and orally bioavailable HIF-2α inhibitor which presents a novel therapeutic option for ccRCC, von Hippel-Lindau disease, and other solid tumors. BPI-452080 is planned to enter Phase I clinical trial in China in early 2023. Citation Format: Pingping Wang, Rongwen Yang, Yun Sun, Xuepeng Ju, Jiayu Zhao, Yanju Liu, Xiaoyun Liu, Zhengyao Zou, Jialin Ren, Min Wang, Haibo Chen, Xuegang Yi, Jian Zhang, Teng Ma, Gaoliang Cheng, Lijia Liu, Jing Guo, Xiangyong Liu, Hong Lan, Lieming Ding, Jiabing Wang. BPI-452080: A potent and selective HIF-2α inhibitor for the treatment of clear cell renal cell carcinoma, von Hippel-Lindau disease, and other solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 494.

Novel Approaches with HIF-2α Targeted Therapies in Metastatic Renal Cell Carcinoma

“…BPI-452080 is a selective small-molecule HIF-2α inhibitor that disrupts HIF-2α heterodimerization with HIF-1β, leading to decreased transcription of downstream hypoxiaresponsive genes (e.g., GLUT1, CCND1, and CXCR4) and VEGFA secretion in pre-clinical RCC models [61]. In RCC tumor xenograft models, oral treatment with BPI-452080 led to a dose-dependent reduction in tumor size [61].…”

“…BPI-452080 is a selective small-molecule HIF-2α inhibitor that disrupts HIF-2α heterodimerization with HIF-1β, leading to decreased transcription of downstream hypoxiaresponsive genes (e.g., GLUT1, CCND1, and CXCR4) and VEGFA secretion in pre-clinical RCC models [61]. In RCC tumor xenograft models, oral treatment with BPI-452080 led to a dose-dependent reduction in tumor size [61]. As of early 2023, a phase 1 clinical trial of BPI-452080 (NCT05843305) is ongoing in China to evaluate the safety and efficacy in patients with mRCC (including VHL-associated mRCC) and other advanced solid tumors.…”