慢性淋巴细胞白血病 (CLL) 患者对 B 细胞淋巴瘤 2 (BCL2) 抑制剂 Venetoclax 的初始治疗反应良好。复发后，他们通常保留对 BCL2 靶向的敏感性，但反应的持久性仍然是一个问题。我们假设同时针对 BCL2 和特大 B 细胞淋巴瘤 (BCLXL) 将是治疗 CLL 的成功策略，包括治疗使用 Venetoclax 复发的患者。为了检验这一假设，我们对 LP-118 进行了临床前研究，LP-118 是一种高效的 BCL2 抑制剂，具有中等的 BCLXL 抑制作用，可最大限度地减少血小板毒性。这项研究表明，LP-118 可在 Venetoclax 幼稚细胞和耐药 CLL 细胞中诱导有效的 BAK 激活、细胞色素 C 释放和细胞凋亡。值得注意的是，LP-118 在表达 BCL2 G101V 突变的细胞系和表达 BCLXL 但缺乏 BCL2 依赖性的细胞中有效。使用免疫活性小鼠模型，Eμ-TCL1、LP-118 表现出低血小板毒性，这阻碍了早期的 BCLXL 抑制剂。最后，RS4;11 和 OSU-CLL 异种移植模型中的 LP-118 分别导致肿瘤负荷降低和生存优势。这些结果为评估 LP-118 治疗 Venetoclax 反应性和复发性 CLL 提供了机制依据。

Patients with chronic lymphocytic leukemia (CLL) respond well to initial treatment with the Bcell lymphoma 2 (BCL2) inhibitor venetoclax. Upon relapse, they often retain sensitivity to BCL2 targeting, but durability of response remains a concern. We hypothesize that targeting both BCL2 and B-cell lymphoma-extra large (BCLXL) will be a successful strategy to treat CLL, including for patients who relapse on venetoclax. To test this hypothesis, we conducted a pre-clinical investigation of LP-118, a highly potent inhibitor of BCL2 with moderate BCLXL inhibition to minimize platelet toxicity. This study demonstrated that LP-118 induces efficient BAK activation, cytochrome C release, and apoptosis in both venetoclax naïve and resistant CLL cells. Significantly, LP-118 is effective in cell lines expressing the BCL2 G101V mutation and in cells expressing BCLXL but lacking BCL2 dependence. Using an immunocompetent mouse model, Eμ-TCL1, LP-118 demonstrates low platelet toxicity, which hampered earlier BCLXL inhibitors. Finally, LP-118 in the RS4;11 and OSU-CLL xenograft models results in decreases in tumor burden and survival advantage, respectively. These results provide a mechanistic rationale for the evaluation of LP-118 for the treatment of venetoclax responsive and relapsed CLL.