APTO-253 (LOR-253)
(Synonyms: LOR-253; LT-253) 目录号 : GC32692
APTO-253 (LOR-253) (LOR-253) 是一种小分子，可抑制 c-Myc 表达，稳定 G-四链体 DNA，并诱导急性髓性白血病细胞的细胞周期停滞和凋亡。
Cas No.:916151-99-0
Sample solution is provided at 25 µL, 10mM.
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Quality Control & SDS
- View current batch:
- Purity: >98.00%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet
| Cell experiment [1]: | |
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Cell lines |
AML cells |
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Preparation Method |
Cells were plated and treated with vehicle DMSO or APTO-253 (LOR-253) (10 concentrations) in 96-well plates for 5 days at 37°C and 5% CO2. Cell viability was measured using CellTiter 96 AQueous one solution (MTS) cell proliferation assay (Promega, catalog #G3581), and IC50 values were calculated using GraphPad Prism 7 software. |
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Reaction Conditions |
10-9-10-4 mM APTO-253 (LOR-253) for 5 days |
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Applications |
APTO-253 (LOR-253) induces cytotoxicity, upregulates p21, and induces G0-G1 cell-cycle arrest in AML cells |
| Animal experiment [2]: | |
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Animal models |
DBA/1J male mice (6 weeks) with collagen induced arthritis (CIA) |
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Preparation Method |
APTO-253 (LOR-253) twice per day for 2 consecutive days per week for 14 days(IV) |
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Dosage form |
15 mg/kg APTO-253 (LOR-253) for 14 days |
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Applications |
APTO-253 (LOR-253) has significant preventive and therapeutic effects on the formation of arthritis. |
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References: [1]: Local A, Zhang H,et,al.APTO-253 Stabilizes G-quadruplex DNA, Inhibits MYC Expression, and Induces DNA Damage in Acute Myeloid Leukemia Cells. Mol Cancer Ther. 2018 Jun;17(6):1177-1186. doi: 10.1158/1535-7163.MCT-17-1209. Epub 2018 Apr 6. PMID: 29626127. |
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APTO-253 is a novel small molecule that exerts potent antitumor activity by inducing Kruppel-like factor 4(KLF4) master transcription factor gene expression, thereby inhibiting cell cycle and leading to programmed cell death. APTO-253 (LOR-253)mediates cancer cell resistance by inducing KLF4. APTO-253 (LOR-253) can treat arthritis [2,3].
In p53-mutated TNBC cells, inhibition of KLF4 by RNA interference reduced NOXA expression. Furthermore, treatment of TNBC cells with a KLF4-inducing small compound, APTO-253, resulted in the induction of NOXA expression and NOXA-mediated apoptosis[4]. APTO-253 (LOR-253) inhibited proliferation in AML cell lines and various forms of lymphoma cell lines with IC50 values ranging from 57 nmol/L to 1.75 μmol/L, APTO-253 (LOR-253) induces cytotoxicity, upregulates p21, and induces G0-G1 cell-cycle arrest in AML cells[1].Enforced KLF4 expression by lentiviral transduction sensitized ovarian cancer cells to the effects of the chemotherapy drugs, paclitaxel and cisplatin. Treatment of ovarian cancer cells with APTO-253 (LOR-253) enhanced the efficacy of both chemotherapy drugs. KLF4 expression mediated by lentiviral vector or induced by APTO-253 (LOR-253) resulted in G1 phase arrest in ovarian cancer cells[5].
In mice，APTO-253 (LOR-253) has significant preventive and therapeutic effects on the formation of arthritis[3]. APTO-253 (LOR-253) has antitumor activity in murine xenograft models of the human solid tumors and was advanced into a phase I clinical trial in patients with advanced solid tumors[6]. In that solid tumor clinical trial, APTO-253 (LOR-253) was well tolerated and produced evidence of antitumor activity in patients with advanced refractory solid tumors but did not produce myelosuppression even at the maximum tested dose. The most common treatment-emergent adverse effects of any grade were rash, peripheral neuropathy, hypersensitivity(<10%), and fatigue[7]
References:
[1]: Local A, Zhang H, et,al. APTO-253 Stabilizes G-quadruplex DNA, Inhibits MYC Expression, and Induces DNA Damage in Acute Myeloid Leukemia Cells. Mol Cancer Ther. 2018 Jun;17(6):1177-1186. doi: 10.1158/1535-7163.MCT-17-1209. Epub 2018 Apr 6. PMID: 29626127.
[2]: Huesca M, Lock LS, et,al. A novel small molecule with potent anticancer activity inhibits cell growth by modulating intracellular labile zinc homeostasis. Mol Cancer Ther. 2009 Sep;8(9):2586-96. doi: 10.1158/1535-7163.MCT-08-1104. Epub 2009 Sep 15. PMID: 19755513.
[3]: Tsuchiya H, Ota M, et,al.Parsing multiomics landscape of activated synovial fibroblasts highlights drug targets linked to genetic risk of rheumatoid arthritis. Ann Rheum Dis. 2021 Apr;80(4):440-450. doi: 10.1136/annrheumdis-2020-218189. Epub 2020 Nov 2. Erratum in: Ann Rheum Dis. 2022 Jan;81(1):e17. PMID: 33139312.
[4]: Nakajima W, Miyazaki K, et,al. Krüppel-Like Factor 4 and Its Activator APTO-253 Induce NOXA-Mediated, p53-Independent Apoptosis in Triple-Negative Breast Cancer Cells. Genes (Basel). 2021 Apr 8;12(4):539. doi: 10.3390/genes12040539. PMID: 33918002; PMCID: PMC8068402.
[5]: Wang B, Shen A, et,al. KLF4 expression enhances the efficacy of chemotherapy drugs in ovarian cancer cells. Biochem Biophys Res Commun. 2017 Mar 11;484(3):486-492. doi: 10.1016/j.bbrc.2017.01.062. Epub 2017 Jan 18. PMID: 28108288.
[6]: William G Rice, Avanish Vellanki, et,al.APTO-253 Induces KLF4 to Promote Potent in Vitro Pro-Apoptotic Activity in Hematologic Cancer Cell Lines and Antitumor Efficacy As a Single Agent and in Combination with Azacitidine in Animal Models of Acute Myelogenous Leukemia (AML),Blood,Volume 124, Issue 21,2014,Page 4813,ISSN 0006-4971,
[7]: Cercek A, Wheler J, et,al. Phase 1 study of APTO-253 HCl, an inducer of KLF4, in patients with advanced or metastatic solid tumors. Invest New Drugs. 2015 Oct;33(5):1086-92. doi: 10.1007/s10637-015-0273-z. Epub 2015 Aug 14. PMID: 26268924.
APTO-253 是一种新型小分子，通过诱导 Kruppel 样因子 4 (KLF4) 主转录因子基因表达，从而抑制细胞周期并导致程序性细胞死亡，发挥强大的抗肿瘤活性。 APTO-253 (LOR-253) 通过诱导 KLF4 介导癌细胞耐药性。 APTO-253 (LOR-253) 可以治疗关节炎[2,3]。
在 p53 突变的 TNBC 细胞中，通过 RNA 干扰抑制 KLF4 会降低 NOXA 的表达。此外，用诱导 KLF4 的小分子化合物 APTO-253 处理 TNBC 细胞，导致诱导 NOXA 表达和 NOXA 介导的细胞凋亡[4]。 APTO-253 (LOR-253) 抑制 AML 细胞系和各种形式的淋巴瘤细胞系的增殖，IC50 值范围为 57 nmol/L 至 1.75 μmol/L，APTO-253 (LOR-253) 诱导细胞毒性，上调 p21，并在 AML 细胞中诱导 G0-G1 细胞周期停滞[1]。通过慢病毒转导增强 KLF4 表达，使卵巢癌细胞对化疗药物紫杉醇和顺铂的作用敏感。用 APTO-253 (LOR-253) 治疗卵巢癌细胞增强了两种化疗药物的疗效。慢病毒载体介导或APTO-253（LOR-253）诱导的KLF4表达导致卵巢癌细胞G1期阻滞[5]。
在小鼠体内，APTO-253（LOR-253）对关节炎的形成具有显着的预防和治疗作用[3]。 APTO-253 (LOR-253) 在人类实体瘤的小鼠异种移植模型中具有抗肿瘤活性，并已进入晚期实体瘤患者的 I 期临床试验[6]。在那项实体瘤临床试验中，APTO-253 (LOR-253) 具有良好的耐受性，并在晚期难治性实体瘤患者中产生了抗肿瘤活性的证据，但即使在最大测试剂量下也不会产生骨髓抑制。最常见的任何级别的治疗紧急不良反应是皮疹、周围神经病变、超敏反应
| Cas No. | 916151-99-0 | SDF | |
| 别名 | LOR-253; LT-253 | ||
| Canonical SMILES | CC(N1)=C(C(N2)=NC3=C2C4=CC=CN=C4C5=NC=CC=C53)C6=C1C=CC(F)=C6 | ||
| 分子式 | C22H14FN5 | 分子量 | 367.38 |
| 溶解度 | DMSO : 33.33 mg/mL (90.72 mM);Water : < 0.1 mg/mL (insoluble) | 储存条件 | Store at -20°C |
| General tips | 请根据产品在不同溶剂中的溶解度选择合适的溶剂配制储备液；一旦配成溶液，请分装保存，避免反复冻融造成的产品失效。 储备液的保存方式和期限：-80°C 储存时，请在 6 个月内使用，-20°C 储存时，请在 1 个月内使用。 为了提高溶解度，请将管子加热至37℃，然后在超声波浴中震荡一段时间。 |
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| Shipping Condition | 评估样品解决方案：配备蓝冰进行发货。所有其他可用尺寸：配备RT，或根据请求配备蓝冰。 | ||
| 制备储备液 | |||
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1 mg | 5 mg | 10 mg |
| 1 mM | 2.722 mL | 13.6099 mL | 27.2198 mL |
| 5 mM | 0.5444 mL | 2.722 mL | 5.444 mL |
| 10 mM | 0.2722 mL | 1.361 mL | 2.722 mL |
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动物平均体重 | g | |
每只动物给药体积 | ul | |
动物数量 | 只 |
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MYC as a target for cancer treatment
Cancer Treat Rev 2021 Mar;94:102154.PMID:33524794DOI:10.1016/j.ctrv.2021.102154.
The MYC gene which consists of 3 paralogs, C-MYC, N-MYC and L-MYC, is one of the most frequently deregulated driver genes in human cancer. Because of its high prevalence of deregulation and its causal role in cancer formation, maintenance and progression, targeting MYC is theoretically an attractive strategy for treating cancer. As a potential anticancer target, MYC was traditionally regarded as undruggable due to the absence of a suitable pocket for high-affinity binding by low molecular weight inhibitors. In recent years however, several compounds that directly or indirectly inhibit MYC have been shown to have anticancer activity in preclinical tumor models. Amongst the most detailed investigated strategies for targeting MYC are inhibition of its binding to its obligate interaction partner MAX, prevention of MYC expression and blocking of genes exhibiting synthetic lethality with overexpression of MYC. One of the most extensively investigated MYC inhibitors is a peptide/mini-protein known as OmoMYC. OmoMYC, which acts by blocking the binding of all 3 forms of MYC to their target promoters, has been shown to exhibit anticancer activity in a diverse range of preclinical models, with minimal side effects. Based on its broad efficacy and limited toxicity, OmoMYC is currently being developed for evaluation in clinical trials. Although no compound directly targeting MYC has yet progressed to clinical testing, APTO-253, which partly acts by decreasing expression of MYC, is currently undergoing a phase I clinical trial in patients with relapsed/refractory acute myeloid leukemia or myelodysplastic syndrome.
APTO-253 Is a New Addition to the Repertoire of Drugs that Can Exploit DNA BRCA1/2 Deficiency
Mol Cancer Ther 2018 Jun;17(6):1167-1176.PMID:29626126DOI:10.1158/1535-7163.MCT-17-0834.
APTO-253 is a small molecule with antiproliferative activity against cell lines derived from a wide range of human malignancies. We sought to determine the mechanisms of action and basis for resistance to APTO-253 so as to identify synthetic lethal interactions that can guide combination studies. The cellular pharmacology of APTO-253 was analyzed in Raji lymphoma cells and a subline selected for resistance (Raji/253R). Using LC/MS/ESI analysis, APTO-253 was found to convert intracellularly to a complex containing one molecule of iron and three molecules of APTO-253 [Fe(253)3]. The intracellular content of Fe(253)3 exceeded that of the native drug by approximately 18-fold, and Fe(253)3 appears to be the most active form. Treatment of cells with APTO-253 caused DNA damage, which led us to ask whether cells deficient in homologous recombination (i.e., loss of BRCA1/2 function) were hypersensitive to this drug. It was found that loss of either BRCA1 or BRCA2 function in multiple isogenic paired cell lines resulted in hypersensitivity to APTO-253 of a magnitude similar to the effects of PARP inhibitors, olaparib. Raji cells selected for 16-fold acquired resistance had 16-fold reduced accumulation of Fe(253)3 RNA-seq analysis revealed that overexpression of the ABCG2 drug efflux pump is a key mechanism of resistance. ABCG2-overexpressed HEK-293 cells were resistant to APTO-253, and inhibition of ABCG2 reversed resistance to APTO-253 in Raji/253R. APTO-253 joins the limited repertoire of drugs that can exploit defects in homologous recombination and is of particular interest because it does not produce myelosuppression. Mol Cancer Ther; 17(6); 1167-76. ©2018 AACR.
APTO-253 Stabilizes G-quadruplex DNA, Inhibits MYC Expression, and Induces DNA Damage in Acute Myeloid Leukemia Cells
Mol Cancer Ther 2018 Jun;17(6):1177-1186.PMID:29626127DOI:10.1158/1535-7163.MCT-17-1209.
APTO-253 is a phase I clinical stage small molecule that selectively induces CDKN1A (p21), promotes G0-G1 cell-cycle arrest, and triggers apoptosis in acute myeloid leukemia (AML) cells without producing myelosuppression in various animal species and humans. Differential gene expression analysis identified a pharmacodynamic effect on MYC expression, as well as induction of DNA repair and stress response pathways. APTO-253 was found to elicit a concentration- and time-dependent reduction in MYC mRNA expression and protein levels. Gene ontogeny and structural informatic analyses suggested a mechanism involving G-quadruplex (G4) stabilization. Intracellular pharmacokinetic studies in AML cells revealed that APTO-253 is converted intracellularly from a monomer to a ferrous complex [Fe(253)3]. FRET assays demonstrated that both monomeric APTO-253 and Fe(253)3 stabilize G4 structures from telomeres, MYC, and KIT promoters but do not bind to non-G4 double-stranded DNA. Although APTO-253 exerts a host of mechanistic sequelae, the effect of APTO-253 on MYC expression and its downstream target genes, on cell-cycle arrest, DNA damage, and stress responses can be explained by the action of Fe(253)3 and APTO-253 on G-quadruplex DNA motifs. Mol Cancer Ther; 17(6); 1177-86. ©2018 AACR.
Phase 1 study of APTO-253 HCl, an inducer of KLF4, in patients with advanced or metastatic solid tumors
Invest New Drugs 2015 Oct;33(5):1086-92.PMID:26268924DOI:10.1007/s10637-015-0273-z.
Introduction: This phase I, multicenter, open-label, single-arm, dose-escalation study evaluated the safety, pharmacokinetics and antitumor activity of APTO-253, an inducer of the transcription factor KLF4, in adults with advanced solid tumors. Methods: APTO-253 was administered IV on days 1 and 2, and 15 and 16 of each 28 day cycle; the dose were escalated from 20 to 387 mg/m(2) in 9 cohorts until DLT was observed. Results: Thirty-two patients were treated on this trial (50 % colon cancer, 22 % other gastrointenstinal malignancies and 18 % non-small cell lung cancer). Fatigue was the only drug-related treatment-emergent adverse event to occur in >10 % of patients. Dose-limiting toxicities of hypersensitivity reaction and transient hypotension despite prophylaxis occurred at 387 mg/m(2) which led to identification of 298 mg/m(2) as the MTD. Only 1 patient had any drug-related treatment-emergent grade 3 adverse event at or below 229 mg/m(2). A total of 21 patients underwent at least one restaging after 2 cycles; 11 patients discontinued prior to the end of cycle 2 due to adverse events (9) or disease progression (2). The best overall response was stable disease (SD) in 5 of these 21 (23.8 %) with durations ranging from 3.6 to 8.4 months. Conclusion: APTO-253 was well tolerated at the Phase 2 recommended dose and produced evidence of antitumor activity in the form of stable disease in patients with advanced solid tumors. Based on the drug levels achieved and the lower frequency of treatment-emergent adverse events encountered, 229 mg/m(2) was selected as the recommended Phase 2 dose. Overall APTO-253 was found to be well tolerated and to have favorable pharmacokinetics, and treatment was associated with stable disease in 5 of 21 (24 %) of patients with far advanced solid tumors.
An in silico investigation of the binding modes and pathway of APTO-253 on c-KIT G-quadruplex DNA
Phys Chem Chem Phys 2021 Feb 7;23(5):3361-3376.PMID:33502401DOI:10.1039/d0cp05210h.
The stability of c-KIT G-quadruplex DNA via ligands has been a significant concern in the growing field of cancer therapy. Thus, it is very important to understand the mechanism behind the high binding affinity of the small drug molecules on the c-KIT G-quadruplex DNA. In this study, we have investigated the binding mode and pathway of the APTO-253 ligand on the c-KIT G-quadruplex DNA employing a total of 10 μs all atom molecular dynamics simulations and further 8.82 μs simulations via the umbrella sampling method using both OL15 and BSC1 latest force fields for DNA structures. From the cluster structure analysis, mainly three binding pathways i.e., top, bottom and side loop stacking modes are identified. Moreover, RMSD, RMSF and 2D-RMSD values indicate that the c-KIT G-quadruplex DNA and APTO-253 molecules are stable throughout the simulation run. Furthermore, the number of hydrogen bonds in each tetrad and the distance between the two central K+ cations confirm that the c-KIT G-quadruplex DNA maintains its conformation in the process of complex formation with the APTO-253 ligand. The binding free energies and the minimum values in the potential of mean forces suggest that the binding processes are energetically favorable. Furthermore, we have found that the bottom stacking mode is the most favorable binding mode among all the three modes for the OL15 force field. However, for the BSC1 force field, both the top and bottom binding modes of the APTO-253 ligand in c-KIT G-quadruplex DNA are comparable to each other. To investigate the driving force for the complex formation, we have noticed that the van der Waals (vdW) and π-π stacking interactions are mainly responsible. Our detailed studies provide useful information for the discovery of novel drugs in the field of stabilization of G-quadruplex DNAs.