DT-061 (SMAP) is an orally administered bioactive activator of protein phosphatase 2A (PP2A) that can be used to study tumors driven by KRAS (Kirsten rat sarcoma viral oncogene, a murine sarcoma virus oncogene) mutations and MYC (myelocytomatosis oncogene, myeloid cell tumor oncogene)[1, 2]. PP2A is an important intracellular regulatory protein, and its dysregulation is associated with the development and progression of various cancers[3]. DT-061 can disrupt the Golgi apparatus and endoplasmic reticulum, as well as lipid synthesis associated with these structures[4].
In vitro, treatment of KRAS mutant H441 and H358 cell lines with DT-061 (5, 10μM) for 3 weeks significantly inhibited cell colony formation and induced intracellular caspase-3/7 activation[5]. Treatment of MDA-MB-231 cells with DT-061 (5μM) for 24h, in combination with calmidazolium, significantly induced apoptosis and intracellular caspase-3/7 activation[6].
In vivo, oral administration of DT-061 (5mg/kg) to mice with H358 or H441 cell xenografts for 4 weeks significantly inhibited tumor growth, with better efficacy when combined with AZD6244. DT-061 also inhibited the expression of p-AKT (protein kinase B, PKB) and MYC in mice[5]. Oral administration of DT-061 (5mg/kg) to mice with heterotopic heart transplantation prolonged survival and suppressed the inflammatory immune response in the transplanted organs[7].
References:
[1] Brautigan D L, Farrington C, Narla G. Targeting protein phosphatase PP2A for cancer therapy: development of allosteric pharmaceutical agents[J]. Clinical Science, 2021, 135(13): 1545-1556.
[2] Farrington C C. Targeted Degradation of the MYC Oncogene Using PP2A-B56alpha Selective Small Molecule Modulators of Proteinphosphatase 2A as a Therapeutic Strategy for Treating Myc-Driven Cancers[M]. Case Western Reserve University, 2020.
[3] Seshacharyulu P, Pandey P, Datta K, et al. Phosphatase: PP2A structural importance, regulation and its aberrant expression in cancer[J]. Cancer letters, 2013, 335(1): 9-18.
[4] Vit G, Duro J, Rajendraprasad G, et al. Chemogenetic profiling reveals PP2A‐independent cytotoxicity of proposed PP2A activators iHAP1 and DT‐061[J]. The EMBO Journal, 2022, 41(14): e110611.
[5] Kauko O, O’Connor C M, Kulesskiy E, et al. PP2A inhibition is a druggable MEK inhibitor resistance mechanism in KRAS-mutant lung cancer cells[J]. Science translational medicine, 2018, 10(450): eaaq1093.
[6] Manoharan G B, Okutachi S, Abankwa D. Potential of phenothiazines to synergistically block calmodulin and reactivate PP2A in cancer cells[J]. PLoS One, 2022, 17(5): e0268635.
[7] Zhou X, Xu Q, Li W, et al. Protein phosphatase 2A activation promotes heart transplant acceptance in mice[J]. Transplantation, 2024, 108(3): e36-e48.
DT-061（SMAP）是一种蛋白磷酸酶2A（PP2A）的口服生物活性激活剂，能够用于KRAS（Kirsten rat sarcoma viral oncogene，一种鼠类肉瘤病毒癌基因）突变和MYC（myelocytomatosis oncogene，骨髓细胞瘤癌基因）驱动的肿瘤的相关研究[1, 2]。PP2A是细胞内一种重要的调控蛋白，其活性失常与多种癌症的发生发展有关[3]。DT-061能够破坏高尔基体和内质网，以及与这些结构相关的脂质合成[4]。
在体外，DT-061（5, 10μM）处理KRAS突变型H441和H358细胞系3周，显著抑制了细胞克隆形成，诱导了细胞内caspase-3/7激活[5]。DT-061（5μM）处理MDA-MB-231细胞24h，在与calmidazolium联合使用的条件下，显著诱导了细胞凋亡和细胞内caspase-3/7激活[6]。
在体内，DT-061（5mg/kg）通过口服治疗H358细胞或H441细胞异种移植小鼠4周，显著抑制了肿瘤体积生长，与AZD6244联合用药的疗效更好，还能够抑制小鼠体内p-AKT（蛋白激酶B，PKB）和MYC的表达[5]。DT-061（5mg/kg）通过口服治疗异位心脏移植模型小鼠，延长了小鼠的存活时间，抑制了移植器官的炎症免疫反应[7]。