Department of Medicine, Division of Hematology-Oncology, Cedars Sinai Medical Center, 8700 Beverly Blvd, Davis 5065, Los Angeles, CA, 90048, USA.
Cancer Biology Program, Cedars-Sinai Cancer, Cedars-Sinai Medical Center, 8700 Beverly Blvd, Los Angeles, CA, 90048, USA.
Chembiochem. 2024 Nov 18;25(22):e202400351. doi: 10.1002/cbic.202400351. Epub 2024 Oct 23.
Aberrantly-active signal transducer and activator of transcription (Stat)3 has a causal role in many human cancers and represents a validated anticancer drug target, though it has posed significant challenge to drug development. A new small molecule, JKB887, was identified through library screening and is predicted to interact with Lys591, Arg609 and Pro63 in the phospho-tyrosine (pTyr)-binding pocket of the Stat3 SH2 domain. JKB887 inhibited Stat3 DNA-binding activity in vitro in a time-dependent manner, with IC of 2.2-4.5 μM at 30-60-min incubation. It directly disrupted both the Stat3 binding to the cognate, high-affinity pTyr (pY) peptide, GpYLPQTV-NH in fluorescent polarization assay with IC of 3.5-5.5 μM at 60-90-min incubation, and to the IL-6 receptor/gp130 or Src in treated malignant cells. Treatment with JKB887 selectively blocked constitutive Stat3 phosphorylation, nuclear translocation and transcriptional activity, and Stat3-regulated gene expression, and decreased viable cell numbers, cell growth, colony formation, migration, and survival in human or mouse tumor cells. By contrast, JKB887 had minimal effects on Stat1, pErk1/2, pShc, pJAK2, or pSrc induction, or on cells that do not harbor aberrantly-active Stat3. Additionally, JKB887 inhibited growth of human breast cancer xenografts in mice. JKB887 is a Stat3-selective inhibitor with demonstrable antitumor effects against Stat3-dependent human cancers.
异常活跃的信号转导子和转录激活子（Stat）3 在许多人类癌症中具有因果关系，是经过验证的抗癌药物靶点，但它给药物开发带来了重大挑战。一种新的小分子 JKB887 通过文库筛选被鉴定出来，预计与 Stat3 SH2 结构域中磷酸酪氨酸（pTyr）结合口袋中的 Lys591、Arg609 和 Pro63 相互作用。JKB887 以时间依赖性方式在体外抑制 Stat3 DNA 结合活性，在 30-60 分钟孵育时 IC 为 2.2-4.5 μM。它直接破坏了 Stat3 与同源高亲和力 pTyr（pY）肽 GpYLPQTV-NH 的结合，在荧光偏振测定中 IC 为 3.5-5.5 μM，孵育 60-90 分钟，以及在处理的恶性细胞中与 IL-6 受体/gp130 或 Src 的结合。用 JKB887 处理可选择性阻断组成型 Stat3 磷酸化、核易位和转录活性以及 Stat3 调节的基因表达，并减少人或鼠肿瘤细胞中的存活细胞数、细胞生长、集落形成、迁移和存活。相比之下，JKB887 对 Stat1、pErk1/2、pShc、pJAK2 或 pSrc 的诱导作用或对不具有异常活跃 Stat3 的细胞几乎没有影响。此外，JKB887 抑制了小鼠人乳腺癌异种移植瘤的生长。JKB887 是一种 Stat3 选择性抑制剂，对依赖 Stat3 的人类癌症具有明显的抗肿瘤作用。
