Reference Detail

Ref Type

Journal Article

PMID

(29282301)

Authors

Gu L, Zhang H, Liu T, Draganov A, Yi S, Wang B, Zhou M

Title

Inhibition of MDM2 by a Rhein-Derived Compound AQ-101 Suppresses Cancer Development in SCID Mice.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Molecular cancer therapeutics	17	2	2018 02	497-507	Mol Cancer Ther

URL

Abstract Text

A novel small-molecule anthraquinone (AQ) analogue, AQ-101, which was synthesized through chemical modification of the core structures of rhein, exhibited potent anticancer activity. In the present study, we evaluated the cancer-inhibiting mechanism of AQ-101 and tested the therapeutic potential of this compound for treating cancer in mice. We found that AQ-101 was able to induce MDM2 protein degradation through a self-ubiquitination and proteasome-mediated mechanism. This AQ-101-induced MDM2 downregulation led to activation of p53, which contributed to apoptosis of acute lymphoblastic leukemia (ALL), especially those with a wild-type p53 phenotype and MDM2 expression in vitro and in vivo When given for a period of 2 weeks (20 mg/kg/day, 3×/week), AQ-101 inhibited development of ALL in nude or SCID mice with a human ALL xenograft and achieved cure by the end of the 5-month experiment. Importantly, AQ-101 showed minimal or no inhibitory effect on normal human hematopoiesis in vitro and was well tolerated in vivo in animal models. Given that MDM2-overexpressing cancers are commonly refractory to current treatment options, our study results suggest that further development of AQ-101 is warranted, as it represents a potentially new, safe anticancer drug with a novel strategy for targeting MDM2. Mol Cancer Ther; 17(2); 497-507. ©2017 AACR.

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Molecular Profile	Treatment Approach

Gene Name	Source	Synonyms	Protein Domains	Gene Description	Gene Role

Therapy Name	Drugs	Efficacy Evidence	Clinical Trials

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description
AQ-101		AQ101\|AQ 101	MDM2 Inhibitor 23	AQ-101 interferes with the interaction between MDM2 and MDM4 and induces degradation of MDM2, resulting in activation of Tp53, and potentially leading to decreased proliferation and increased apoptosis of tumor cells (PMID: 29282301).

Gene	Variant	Impact	Protein Effect	Variant Description	Associated with drug Resistance

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
MDM2 over exp TP53 wild-type	acute lymphoblastic leukemia	sensitive	AQ-101	Preclinical - Cell line xenograft	Actionable	In a preclinical study, AQ-101 inhibited growth and induced apoptosis in acute lymphocytic leukemia (ALL) cell lines with wild-type TP53 and overexpression of MDM2 in culture, and inhibited development of leukemia in ALL cell line xenograft models (PMID: 29282301).	29282301