PRIMA-1MET is a small molecule organic compound that can restore tumor suppression function, mainly targeting mutant p53 and inducing cell death in various types of cancer cells[1]. PRIMA-1MET is hydrolyzed into the active form of methylquinine cycloketone within cells and covalently binds to the thiol group of the core domain of the mutant p53 protein, thereby causing structural changes and restoring the active conformation of p53 protein [2]. PRIMA-1MET has been widely used in anti-cancer research[3].
In vitro, PRIMA-1MET inhibits the cell viability of BWM-1 cells (IC50 value=30μM) and MWCL-1 cells (IC50 value= 28μM) after treatment of 48 hours[4]. PRIMA-1MET treatment (60µM) for 24 hours significant induced autophagy and enhanced the mTOR/AMPK-ULK1-Vps34 autophagic signaling cascade in colorectal cancer (CRC) cells[5]. PRIMA-1 MET (100μM; 72H) effectively inhibited the growth of small cell lung cancer (SCLC) cell lines expressing mutant p53 induced apoptosis, accompanied by an increase in the proportion of DNA fragmented cells, caspase-3 activation, and downregulation of Bcl-2 expression[6].
In vivo, PRIMA-1MET treatment (100mg/kg/day; i.p.) for 15 consecutive days can inhibit the growth of multiple myeloma tumors containing mutant p53 in multiple myeloma xenograft SCID mouse models[7]. Intraperitoneal injection of PRIMA-1MET at the dosage of 100mg/kg/day for 5 consecutive days significantly reduced the tumor size and tumor volume in the mouse model of rectal cancer xenograft tumors, decreased ERK1/2 phosphorylation, and inhibited MEK activity[8].
References:
[1] Perdrix, A.; Najem, A.; Saussez, S.; Awada, A.; Journe, F.; Ghanem, G.; Krayem, M. PRIMA-1 and PRIMA-1Met (APR-246): From Mutant/Wild Type p53 Reactivation to Unexpected Mechanisms Underlying Their Potent Anti-Tumor Effect in Combinatorial Therapies. Cancers 2017, 9, 172.
[2] Xie X, Fan C, Luo B, et al. APR-246 enhances colorectal cancer sensitivity to radiotherapy[J]. Molecular cancer therapeutics, 2023, 22(8): 947-961.
[3] Menichini P, Monti P, Speciale A, et al. Antitumor effects of PRIMA-1 and PRIMA-1Met (APR246) in hematological malignancies: still a mutant p53-dependent affair?[J]. Cells, 2021, 10(1): 98.
[4] Sobhani M, Kwan K, Saha M N, et al. Small molecule PRIMA-1 met sensitizes Waldenstrom macroglobulinemia cells to apoptosis and displays synergistic cytotoxicity with bortezomib[J]. Blood, 2013, 122(21): 5143.
[5] Li X L, Zhou J, Xia C J, et al. PRIMA-1met induces autophagy in colorectal cancer cells through upregulation of the mTOR/AMPK-ULK1-Vps34 signaling cascade[J]. Oncology Reports, 2021, 45(5): 86.
[6] Zandi R, Selivanova G, Christensen C L, et al. PRIMA-1Met/APR-246 induces apoptosis and tumor growth delay in small cell lung cancer expressing mutant p53[J]. Clinical Cancer Research, 2011, 17(9): 2830-2841.
[7] Saha M N, Jiang H, Yang Y, et al. PRIMA-1Met/APR-246 displays high antitumor activity in multiple myeloma by induction of p73 and Noxa[J]. Molecular cancer therapeutics, 2013, 12(11): 2331-2341.
[8] Lu T, Zou Y, Xu G, et al. PRIMA-1Met suppresses colorectal cancer independent of p53 by targeting MEK[J]. Oncotarget, 2016, 7(50): 83017.
PRIMA-1MET是一种能够恢复肿瘤抑制功能的小分子有机化合物，主要靶向突变型p53，诱导多种癌细胞死亡[1]。PRIMA-1MET在细胞内水解为活性形式的甲基喹啉环酮，并通过共价结合突变p53蛋白核心结构域的巯基，引发构象改变并恢复p53蛋白活性[2]。PRIMA-1MET已被广泛应用于抗癌研究领域[3]。
在体外，处理48小时后，PRIMA-1MET可抑制BWM-1细胞（IC50=30μM）和MWCL-1细胞（IC50=28μM）的活性[4]。在结直肠癌细胞中，60µM浓度的PRIMA-1MET处理24小时显著诱导自噬，并增强mTOR/AMPK-ULK1-Vps34自噬信号通路[5]。100μM 浓度的PRIMA-1MET处理72小时能有效抑制表达突变p53的小细胞肺癌（SCLC）细胞系生长，诱导细胞凋亡，伴随着DNA片段化细胞比例增加，caspase-3激活及Bcl-2表达下调[6]。
在体内，连续15天的PRIMA-1MET（100mg/kg/day；i.p）处理可抑制多发性骨髓瘤SCID小鼠移植瘤模型中含突变p53的肿瘤生长[7]。在直肠癌移植瘤小鼠模型中，连续5天腹腔注射PRIMA-1MET（100mg/kg/day）显著减小肿瘤体积，降低ERK1/2磷酸化水平并抑制MEK活性[8]。