TDRL-551

TDRL-551 is a potent inhibitor of replication protein A (RPA) with an IC₅₀ value of 18µM^[1]. RPA is an important single-stranded DNA (ssDNA) binding protein complex in eukaryotes and plays an important role in multiple key biological processes such as DNA replication, repair, damage response, telomere maintenance and viral defense^{[2, 3]}. TDRL-551 can inhibit RPA-DNA interaction and improve the efficacy of platinum-based chemotherapy for lung and ovarian cancer^[4].

In vitro, TDRL-551 (0-200μM) treatment of H460, SKOV-3, A2780 and OVCA-429 cells for 48h inhibited cell viability in a dose-dependent manner^[1]. TDRL-551 (0-20μM) treatment of human non-small cell lung cancer cell line H460 cells for 24h induced cell death in a dose-dependent manner, but without caspase activation, indicating that TDRL-551-induced cell death is a non-apoptotic mechanism^[5].

In vivo, TDRL-551 (200mg/kg) was intraperitoneally injected into mice bearing non-small cell lung cancer (NSCLC) cell xenografts for 20 days, significantly inhibiting tumor growth in the mice, with an effect comparable to that of carboplatin. The combination of the two had a better effect^[6].

References:
[1] Mishra A K, Dormi S S, Turchi A M, et al. Chemical inhibitor targeting the replication protein A–DNA interaction increases the efficacy of Pt-based chemotherapy in lung and ovarian cancer[J]. Biochemical pharmacology, 2015, 93(1): 25-33.
[2] Dueva R, Iliakis G. Replication protein A: a multifunctional protein with roles in DNA replication, repair and beyond[J]. NAR cancer, 2020, 2(3): zcaa022.
[3] Zou Y U E, Liu Y, Wu X, et al. Functions of human replication protein A (RPA): from DNA replication to DNA damage and stress responses[J]. Journal of cellular physiology, 2006, 208(2): 267-273.
[4] Gavande N S, VanderVere-Carozza P S, Hinshaw H D, et al. DNA repair targeted therapy: The past or future of cancer treatment?[J]. Pharmacology & therapeutics, 2016, 160: 65-83.
[5] VanderVere-Carozza P S, Gavande N S, Jalal S I, et al. In vivo targeting replication protein A for cancer therapy[J]. Frontiers in Oncology, 2022, 12: 826655.
[6] Mishra A K. Developing small molecule inhibitors targeting Replication Protein A for platinum-based combination therapy[D]. , 2014.

TDRL-551是一种有效的复制蛋白A（RPA）抑制剂，IC₅₀值为18µM^[1]。RPA是真核生物中一种重要的单链DNA（ssDNA）结合蛋白复合物，在DNA复制、修复、损伤应答、端粒维持及病毒防御等多个关键生物学过程中发挥重要作用^{[2, 3]}。TDRL-551能够抑制RPA-DNA相互作用，提高以铂为基础的肺癌和卵巢癌化疗的疗效^[4]。

在体外，TDRL-551（0-200μM）处理H460、SKOV-3、A2780和OVCA-429细胞48h，均以剂量依赖性方式抑制了细胞的活力^[1]。TDRL-551（0-20μM）处理人非小细胞肺癌细胞系H460细胞24h，以剂量依赖性方式诱导了细胞死亡，但没有伴随胱天蛋白酶活化，表明TDRL-551诱导的细胞死亡是一种非凋亡机制^[5]。

在体内，TDRL-551（200mg/kg）通过腹腔注射治疗非小细胞肺癌（NSCLC）细胞异种移植的小鼠20天，显著抑制了小鼠体内肿瘤的生长，效果与卡铂（Carboplatin）相当，二者联合治疗效果更好^[6]。