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].
APTO-253 细胞实验
Cell Line
Concentration
Treated Time
Description
References
mouse aortic vascular smooth muscle cells (MOVAS)
5 µM
24 h
APTO-253 reversed the inhibitory effects of quercetin on ox-LDL-induced KLF4-mediated phenotypic switch in MOVAS, increasing lipid accumulation and cholesterol uptake.
Int J Mol Sci. 2024 Jul 15;25(14):7755
Corpus cavernosum smooth muscle cells (CCSMCs)
5 µM
48 h
APTO-253, as an inducer of KLF4, was introduced for rescue experiments in CCSMCs under the co-culture system
World J Mens Health. 2024 Jul;42(3):638-649
Caco-2 cells
1 µM
24 h
APTO-253 significantly increased the protein expression of KLF4 in Caco-2 cells, improved TEER and decreased FD4 permeability, and upregulated the protein expression of E-cadherin, Occludin, ZO-1, and Claudin-4
Cell Mol Life Sci. 2024 Nov 29;81(1):470
HCT116 cells
1 µM
24 h
Increased γ-H2AFX accumulation in BRCA2-deficient cells
Mol Cancer Ther. 2018 Jun;17(6):1167-1176
MCF7 cells
20 µM
24 h
Increased γ-H2AFX accumulation in BRCA1-deficient cells
Mol Cancer Ther. 2018 Jun;17(6):1167-1176
CAOV3 ovarian carcinoma cells
1 µM
24 h
Detected γ-H2AFX foci formation, showing APTO-253 caused DNA damage
Mol Cancer Ther. 2018 Jun;17(6):1167-1176
TALL-1 cells
50 nM
72 h
APTO-253 induced KLF4 expression and suppressed NOTCH3 expression, promoting differentiation of TALL-1 cells into CD4 single-positive cells followed by apoptotic cell death
FASEB J. 2025 May 31;39(10):e70613
MDSCs
50 nM
72 h
To evaluate the effect of APTO-253 on KLF4 expression in MDSCs and its regulation of Th17 cell differentiation. Results showed that APTO-253 treatment increased KLF4 expression in MDSCs and reduced Th17 cell numbers.
J Diabetes Res. 2021 Sep 15;2021:7945117
APTO-253 动物实验
Species
Animal Model
Administration
Dosage
Frequency
Description
References
Ob/ob mice
Pressure ulcer model
Intraperitoneal injection
1 mg/kg
Every other day until day 8
To evaluate the effect of APTO-253 on diabetic wound healing. Results showed that APTO-253 significantly accelerated wound healing, increased MDSC populations, and reduced Th17 cell numbers.
搜索
