Reference Detail

Ref Type

Journal Article

PMID

(26883273)

Authors

Karan G, Wang H, Chakrabarti A, Karan S, Liu Z, Xia Z, Gundluru M, Moreton S, Saunthararajah Y, Jackson MW, Agarwal MK, Wald DN

Title

Identification of a Small Molecule That Overcomes HdmX-Mediated Suppression of p53.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Molecular cancer therapeutics	15	4	2016 Apr	574-582	Mol Cancer Ther

URL

Abstract Text

Inactivation of the p53 tumor suppressor by mutation or overexpression of negative regulators occurs frequently in cancer. As p53 plays a key role in regulating proliferation or apoptosis in response to DNA-damaging chemotherapies, strategies aimed at reactivating p53 are increasingly being sought. Strategies to reactivate wild-type p53 include the use of small molecules capable of releasing wild-type p53 from key, cellular negative regulators, such as Hdm2 and HdmX. Derivatives of the Hdm2 antagonist Nutlin-3 are in clinical trials. However, Nutlin-3 specifically disrupts Hdm2-p53, leaving tumors harboring high levels of HdmX resistant to Nutlin-3 treatment. Here, we identify CTX1, a novel small molecule that overcomes HdmX-mediated p53 repression. CTX1 binds directly to HdmX to prevent p53-HdmX complex formation, resulting in the rapid induction of p53 in a DNA damage-independent manner. Treatment of a panel of cancer cells with CTX1 induced apoptosis or suppressed proliferation and, importantly, CTX1 demonstrates promising activity as a single agent in a mouse model of circulating primary human leukemia. CTX1 is a small molecule HdmX inhibitor that demonstrates promise as a cancer therapeutic candidate. Mol Cancer Ther; 15(4); 574-82. ©2016 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
CTX-1	CTX-1	4	0

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description
CTX-1		CTX1	MDM4 inhibitor 8	CTX-1 binds to and inhibits Mdm4 (MdmX), which disrupts the interaction between Tp53 and Mdm4, leading to stabilization of Tp53 and potentially leading to increased tumor cell death (PMID: 26883273).

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
TP53 loss	Advanced Solid Tumor	decreased response	CTX-1	Preclinical	Actionable	In a preclinical study, CTX-1 induced cell death in TP53-deficient human tumor cell lines in culture, but had a greater effect on cell lines with wild-type TP53 compared to isogenic cell lines with TP53 loss (PMID: 26883273).	26883273
TP53 wild-type	acute myeloid leukemia	sensitive	CTX-1 + Nutlin-3a	Preclinical	Actionable	In a preclinical study, the combination of CTX-1 and Nutlin-3 resulting in improved survival time in mouse models of acute myeloid leukemia using TP53 wild-type primary human acute myeloid leukemia cells (PMID: 26883273).	26883273
TP53 wild-type	acute myeloid leukemia	sensitive	CTX-1	Preclinical	Actionable	In a preclinical study, CTX-1 improved survival time in mouse models of acute myeloid leukemia using TP53 wild-type primary human acute myeloid leukemia cells (PMID: 26883273).	26883273
TP53 wild-type	Advanced Solid Tumor	sensitive	CTX-1	Preclinical	Actionable	In a preclinical study, CTX-1 induced cell death in several solid tumor cell lines with wild-type TP53 in culture (PMID: 26883273).	26883273
TP53 wild-type	Advanced Solid Tumor	sensitive	CTX-1 + Nutlin-3a	Preclinical	Actionable	In a preclinical study, CTX-1 and Nutlin-3 worked cooperatively to induce cell death in several TP53 wild-type human tumor cell lines in culture (PMID: 26883273).	26883273
TP53 mutant	Advanced Solid Tumor	sensitive	CTX-1	Preclinical	Actionable	In a preclinical study, CTX-1 induced increased Tp53 protein levels and cell death in human tumor cell lines with mutant Tp53 in culture (PMID: 26883273).	26883273