APTO-253 (LOR-253) (Synonyms: APTO-253)

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.