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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 Molecular cancer therapeutics
Vol 15
Issue 4
Date 2016 Apr
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 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 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
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 + 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 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 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