YL0712-3, a Novel ATR/ATM Inhibitor, Demonstrates Anti-Tumor Activity in TP53 Mutant DLBCL through Synthetic Lethality and Degradation of Mutant p53

作者：Li Wang, Guo Zhang, Hui Zhou, Ting Niu · 发表于：Blood · 年份：2024 · DOI：10.1182/blood-2024-207718 · 被引用次数：2 · 研究领域：Cytokine Signaling Pathways and Interactions

Background: Patients with diffuse large B-cell lymphoma (DLBCL) harboring TP53 mutations (TP53mut DLBCL) face a dismal prognosis and currently lack a standardized treatment regimen. Both ATR (Ataxia Telangiectasia and Rad3-related protein) and ATM (Ataxia Telangiectasia Mutated) are reported to have synthetic lethal interactions with TP53, suggesting that inhibition of ATR/ATM could induce synthetic lethality in TP53 mutant tumor cells. Furthermore, mutant p53 proteins (mutp53) not only lose the tumor suppressive functions of wild-type p53 but also acquire gain-of-function (GOF) properties, making the degradation of mutp53 a promising therapeutic approach. Objective: This study aims to identify and evaluate the therapeutic efficacy and mechanisms of a novel ATM/ATR inhibitor, YL0712-3, targeting TP53 mutant DLBCL. Methods: A small molecule library was constructed based on proprietary core structure, from which we screened and further optimized a small molecule designated as YL0712-3. The kinase profile of YL0712-3 was screened and its downstream pathways (ATM/Chk2 and ATR/Chk1) were validated via Western Blot. The in vitro activity of YL0712-3 was assessed across various TP53 mutant and wild-type DLBCL cell lines, with ATR inhibitor Elimusertib and ATM inhibitor AZD1390 as positive controls. The in vivo efficacy of YL0712-3 was evaluated using cell-derived xenograft (CDX) and patient-derived xenograft (PDX) mouse models. Additionally, YL0712-3 + R-CHOP regimen was evaluated i...