生物活性

• 描述The p21 Activated Kinases (PAKs) are a family of serine threonine kinases, that consist of 6 members, PAKs 1-6, which are positioned at an intersection of multiple signaling pathways implicated in oncogenesis^[2]. 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. APTO-253 was found to elicit a concentration- and time-dependent reduction in MYC mRNA expression and protein levels. Intracellular pharmacokinetic studies in AML cells revealed that APTO-253 is converted intracellularly from a monomer to a ferrous complex [Fe(253)3]^[3]. 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^[4]. Treatment of ovarian cancer cells with APTO-253, a small molecule inducer of KLF4, enhanced the efficacy of both chemotherapy drugs. KLF4 expression mediated by lentiviral vector or induced by APTO-253 resulted in G1 phase arrest in ovarian cancer cells^[5].
• 临床研究

• NCT号	适应症或疾病	临床期	招募状态	预计完成时间	地点
  NCT02267863	Acute Myelogenous Leukemia in ... more >>Relapse Acute Myelogenous Leukemia, Relapsed, Adult Acute Myelogenous Leukemia, Adult Acute Myelogenous Leukemia High Risk Myelodysplasia Collapse <<	Phase 1	Recruiting	June 2020	United States, Arizona ... more >> University of Arizona Cancer Center Recruiting Tucson, Arizona, United States, 85724 Contact: Crystal Placencia    520-694-1231    CPlacencia@uacc.arizona.edu    Contact: Melissa Lim    520-626-9526    mlim@uacc.arizona.edu    Principal Investigator: Daruka Mahadevan, M.D          Sub-Investigator: Hani Babiker, M.D          Sub-Investigator: Sandra Kurtin, ANP-C          Sub-Investigator: Lois Lattimore, ANP-C          Sub-Investigator: Keri Maher, DO          Sub-Investigator: Laura McPheeters, FNP          United States, Michigan University of Michigan Not yet recruiting Ann Arbor, Michigan, United States, 48109 Principal Investigator: Patrick Burke, MD          United States, Ohio University Hospital Not yet recruiting Cleveland, Ohio, United States, 44106 Contact: Donna Kane, RN    216-844-8123    donna.kane@UHhospitals.org    United States, Texas Baylor Research Institute Recruiting Dallas, Texas, United States, 75246 Contact: Erica Goetz, RN, BSN    214-818-8325    erica.goetz@baylorhealth.edu    Principal Investigator: Moshe Y. Levy, MD          MD Anderson Cancer Center Not yet recruiting Houston, Texas, United States, 77030 Principal Investigator: Maro Ohanian, DO Collapse <<

• 参考文献

• [1] Sakata VM, da Silva FT, et al. High rate of clinical recurrence in patients with Vogt-Koyanagi-Harada disease treated with early high-dose corticosteroids. Graefes Arch Clin Exp Ophthalmol. 2015 May;253(5):785-90.

  [2] Chetan K Rane,et al. P21 activated kinase signaling in cancer. Semin Cancer Biol. 2019 Feb;54:40-49.

  [3] Andrea Local,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.

  [4] Cheng-Yu Tsai,et al. 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.

  [5] Baojin Wang,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.

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