Targeting RECQL5 Functions, by a Small Molecule, Selectively Kills Breast Cancer in Vitro and in Vivo
Targeting RECQL5 Functions, by a Small Molecule, Selectively Kills Breast Cancer in Vitro and in Vivo
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DOI：
10.1021/acs.jmedchem.0c01692
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发表时间：
2021-02-02
影响因子：
7.3
通讯作者：
Patro, Birija Sankar
中科院分区：
文献类型：
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作者：
Chakraborty, Saikat;Dutta, Kartik;Patro, Birija Sankar
临床和临床前资料表明，RECQL5蛋白在乳腺癌中的过度表达与不良预后、生存期和治疗耐药密切相关。在目前的研究中，我们报道了一个小分子4a的设计、合成和特异性，它可以优先杀死表达RECQL5的乳腺癌，而不是RECQL5基因敲除。我们的严格分析表明，化合物4a特异性地敏化表达RECQL5的癌症，而它对DNA RECQL解旋酶的其他成员没有任何影响。有机合成、生化、电子分子模拟、基因敲除、功能突变和挽救实验的综合方法表明，4a有效地抑制RECQL5-解旋酶的活性，稳定RECQL5-RAD51的物理相互作用，导致HRR受损和对表达RECQL5的乳腺癌的优先杀伤。此外，4a治疗导致对顺铂耐药的乳腺癌有效增敏，但不能使正常乳腺上皮细胞增敏。在药理上，化合物4a对裸鼠体内表达RECQL5的乳腺肿瘤(人异种移植瘤)生长有抑制作用，对重要器官无明显毒性。
Clinical and preclinical data reveal that RECQL5 protein overexpression in breast cancer was strongly correlated with poor prognosis, survival, and therapeutic resistance. In the current investigation, we report design, synthesis, and specificity of a small molecule, 4a, which can preferentially kill RECQL5-expressing breast cancers but not RECQL5 knockout. Our stringent analysis showed that compound 4a specifically sensitizes RECQL5-expressing cancers, while it did not have any effect on other members of DNA RECQL-helicases. Integrated approaches of organic synthesis, biochemical, in silico molecular simulation, knockouts, functional mutation, and rescue experiments showed that 4a potently inhibits RECQL5-helicase activity and stabilizes RECQL5-RAD51 physical interaction, leading to impaired HRR and preferential killing of RECQL5-expressing breast cancer. Moreover, 4a treatment led to the efficient sensitization of cisplatin-resistant breast cancers but not normal mammary epithelial cells. Pharmacologically, compound 4a was orally effective in reducing the growth of RECQL5-expressing breast tumors (human xenograft) in NUDE-mice with no appreciable toxicity to the vital organs.