Velcrin molecular glues induce apoptosis in glioblastomas with high PDE3A and SLFN12 expression

Abstract

Velcrins are molecular glues that kill cells by inducing the formation of a protein complex between the RNase SLFN12 and the phosphodiesterase PDE3A. Formation of the complex activates SLFN12, which cleaves tRNALeu(TAA) and induces apoptosis. Velcrins such as the clinical investigational compound, BAY 2666605, were found to have activity across multiple solid tumors cell lines from the Cancer Cell Line Encyclopedia (CCLE), including glioblastoma cell lines. We therefore aim to characterize velcrins as novel therapeutic agents in glioblastoma. PDE3A and SLFN12 expression levels were measured in glioblastoma cell lines, TCGA tumor samples and tumor neurospheres. Velcrin-treated cells were assayed for viability, induction of apoptosis, cell cycle phases, and global changes in translation. Transcriptional profiling of the cells was obtained. Xenograft-harboring mice treated with velcrins were also monitored for survival. We identified several velcrin-sensitive glioblastoma cell lines and four velcrin-sensitive glioblastoma patient-derived models. We determined that BAY 2666605 crosses the blood brain barrier and elicits full tumor regression in an orthotopic xenograft model of GB1 cells. We also determined that the velcrins BAY 2666605 and BRD3800 induce tumor regression in subcutaneous glioblastoma PDX models. Velcrins have anti-tumor activity in preclinical models of glioblastoma, warranting further investigation as potential therapeutic agents.