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|Ref Type||Journal Article|
|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.|
|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.|
|Molecular Profile||Treatment Approach|
|Gene Name||Source||Synonyms||Protein Domains||Gene Description||Gene Role|
|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 + 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|
|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|