Bioorganic Chemistry Laboratory, New Chemistry Unit, Jawaharlal Nehru Centre for Advanced Scientific Research, Jakkur P.O., Bengaluru 560064, Karnataka, India.
Department of Theoretical Chemistry and Biology, KTH Royal Institute of Technology, S-106 91, Stockholm, Sweden.
Theranostics. 2020 Aug 20;10(23):10394-10414. doi: 10.7150/thno.48675. eCollection 2020.
The selective recognition and imaging of oncogene specific G-quadruplex (GQ) structures holds great promise in the development of diagnostic therapy (theranostics) for cancer and has been challenging due to their structural dynamics and diversity. We report selective recognition of GQ by a small molecule through unique hybrid loop stacking and groove binding mode with turn on far-red fluorescence response and anticancer activity demonstrating the potential implications for GQ-targeted cancer theranostics. Biophysical investigation reveal the turn on far-red emission property of TGP18 for selective recognition of GQ. studies including DNA damage and oxidative stress evaluation guided us to perform (3D spheroid) and (xenograft mice model) anti-cancer activity, and tumor tissue imaging to assess the theranostic potential of TGP18. Neocuproine-based far-red turn on fluorescence probe TGP18 shows GQ-to-duplex selectivity and specifically recognizes BCL-2 GQ with high affinity through a unique hybrid binding mode involving loop-stacking and groove interactions. Our study reveals that the selective recognition originating from the distinct loop structure of GQ that alters the overall probe interaction and binding affinity. TGP18 binding to anti-apoptotic BCL-2 GQ ablates the pro-survival function and elicit anti-cancer activity by inducing apoptosis in cancer cells. We deciphered that inhibition of BCL-2 transcription synergized with signaling cascade of nucleolar stress, DNA damage and oxidative stress in triggering apoptosis signaling pathway. Intervention of GQ mediated lethality by TGP18 has translated into anti-cancer activity in both 3D spheroid culture and xenograft models of lung and breast cancer with superior efficacy for the former. therapeutic efficacy supplemented with tumor 3D spheroid and tissue imaging potential define the role of TGP18 in GQ-targeted cancer theranostics.
小分子通过独特的杂环堆积和沟槽结合模式选择性识别 G-四链体（GQ）结构，并具有远红色荧光响应和抗癌活性，为 GQ 靶向癌症治疗学的发展带来了新的契机。本研究报告了一种小分子通过独特的杂环堆积和沟槽结合模式选择性识别 GQ 的能力，该模式具有远红色荧光响应和抗癌活性，为 GQ 靶向癌症治疗学的发展带来了新的契机。生物物理研究揭示了 TGP18 对 GQ 的远红色发射特性。通过 DNA 损伤和氧化应激评估指导的研究，我们进行了（3D 球体）和（异种移植小鼠模型）抗癌活性以及肿瘤组织成像，以评估 TGP18 的治疗潜力。基于邻菲啰啉的远红色荧光开启探针 TGP18 显示出 GQ 对双链体的选择性，并通过涉及环堆叠和沟槽相互作用的独特杂化结合模式特异性识别 BCL-2 GQ，具有高亲和力。我们的研究表明，选择性识别源于 GQ 的独特环结构，改变了整体探针相互作用和结合亲和力。TGP18 与抗凋亡 BCL-2 GQ 结合，通过诱导癌细胞凋亡，破坏其促生存功能并发挥抗癌活性。我们揭示了 BCL-2 转录的抑制与核仁应激、DNA 损伤和氧化应激的信号级联协同作用，触发凋亡信号通路。TGP18 通过干预 GQ 介导的致死性，在 3D 球体培养和肺癌和乳腺癌的异种移植模型中均显示出抗癌活性，前者的疗效更为显著。治疗效果辅以肿瘤 3D 球体和组织成像潜力，明确了 TGP18 在 GQ 靶向癌症治疗学中的作用。
