BFL1, a member of the antiapoptotic BCL2 family, has been relatively understudied compared to its counterparts despite evidence of its overexpression in various hematological malignancies. Across two articles, we describe the development of BFL1 in vivo tools. The first article describes the hit identification from a covalent fragment library and the subsequent evolution from the hit to compound 6.²² This work reports the structure-based optimization of compound 6 into a series of BFL1 inhibitors selective over the other BCL2 family members, with low nanomolar cellular activity when combined with AZD5991, exemplified by compound 20. Compound 20 demonstrated a cell death phenotype in SUDHL1 and OCILY10 cell lines and in the in vivo study, BFL1 stabilization and cleaved caspase 3 activation were observed in a dose-dependent manner. In addition, the enzymatic turnover studies with the BFL1 protein showed that compound 20 stabilized the protein, extending the half-life to 10.8 h.

中文翻译：

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基于结构的一系列共价、口服生物利用度和选择性 BFL1 抑制剂的发现


BFL1 是抗凋亡 BCL2 家族的一员，尽管有证据表明其在各种血液系统恶性肿瘤中过表达，但与同类产品相比，BFL1 的研究相对不足。在两篇文章中，我们描述了 BFL1 体内工具的开发。第一篇文章描述了来自共价片段库的苗头化合物鉴定以及随后从苗头化合物到化合物 6 的演变。²² 这项工作报道了化合物 6 基于结构的优化成一系列 BFL1 抑制剂，这些抑制剂对其他 BCL2 家族成员具有选择性，当与 AZD5991 结合时具有低纳摩尔细胞活性，以化合物 20 为例。化合物 20 在 SUDHL1 和 OCILY10 细胞系中表现出细胞死亡表型，在体内研究中，以剂量依赖性方式观察到 BFL1 稳定和裂解的 caspase 3 激活。此外，BFL1 蛋白的酶周转研究表明，化合物 20 稳定了蛋白质，将半衰期延长至 10.8 小时。