Bio-Organic Division, Bhabha Atomic Research Centre, Trombay, Mumbai 400085, India.
Homi Bhabha National Institute, Anushaktinagar, Mumbai 400094, India.
J Med Chem. 2021 Feb 11;64(3):1524-1544. doi: 10.1021/acs.jmedchem.0c01692. Epub 2021 Feb 2.
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, , which can preferentially kill RECQL5-expressing breast cancers but not RECQL5 knockout. Our stringent analysis showed that compound 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, molecular simulation, knockouts, functional mutation, and rescue experiments showed that potently inhibits RECQL5-helicase activity and stabilizes RECQL5-RAD51 physical interaction, leading to impaired HRR and preferential killing of RECQL5-expressing breast cancer. Moreover, treatment led to the efficient sensitization of cisplatin-resistant breast cancers but not normal mammary epithelial cells. Pharmacologically, compound 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.
临床前和临床数据表明，乳腺癌中 RECQL5 蛋白的过表达与不良预后、生存和治疗耐药性密切相关。在本研究中，我们报告了一种小分子 的设计、合成和特异性，它可以优先杀死表达 RECQL5 的乳腺癌细胞，而不会杀死 RECQL5 敲除细胞。我们严格的分析表明，化合物 特异性地使表达 RECQL5 的癌症敏感，而对其他 DNA RECQL 解旋酶成员没有任何影响。综合运用有机合成、生物化学、分子模拟、基因敲除、功能突变和拯救实验的方法表明， 能够有效地抑制 RECQL5 解旋酶活性，并稳定 RECQL5-RAD51 物理相互作用，导致 HRR 受损，从而优先杀死表达 RECQL5 的乳腺癌细胞。此外， 治疗导致顺铂耐药乳腺癌的有效敏感性增加，而对正常乳腺上皮细胞没有影响。药理学研究表明，化合物 在 NUDE 小鼠中具有口服活性，能够减少表达 RECQL5 的乳腺癌肿瘤（人异种移植）的生长，而对重要器官没有明显的毒性。
