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