title: Identification of a Small Molecule That Overcomes HdmX-Mediated Suppression of p53.
abstract: 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.
authors.affiliation: Invenio Therapeutics, Lexington, KY.
authors.forename: Goutam
authors.initials: G
authors.lastname: Karan
authors.affiliation: Department of Hematology, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China.
authors.forename: Huaiyu
authors.initials: H
authors.lastname: Wang
authors.affiliation: Invenio Therapeutics, Lexington, KY.
authors.forename: Amit
authors.initials: A
authors.lastname: Chakrabarti
authors.affiliation: Invenio Therapeutics, Lexington, KY.
authors.forename: Sukanya
authors.initials: S
authors.lastname: Karan
authors.affiliation: Department of Pathology, Case Western Reserve University and University Hospitals Case Medical Center, Cleveland, OH.
authors.forename: Zhigang
authors.initials: Z
authors.lastname: Liu
authors.affiliation: Invenio Therapeutics, Lexington, KY.
authors.forename: Zhiqiang
authors.initials: Z
authors.lastname: Xia
authors.affiliation: Invenio Therapeutics, Lexington, KY.
authors.forename: Mahesh
authors.initials: M
authors.lastname: Gundluru
authors.affiliation: Invenio Therapeutics, Lexington, KY.
authors.forename: Stephen
authors.initials: S
authors.lastname: Moreton
authors.affiliation: Department of Translational Hematology & Oncology Research, Cleveland Clinic Foundation, Cleveland, OH.
authors.forename: Yogen
authors.initials: Y
authors.lastname: Saunthararajah
authors.affiliation: Department of Pathology, Case Western Reserve University and University Hospitals Case Medical Center, Cleveland, OH.
authors.forename: Mark W
authors.initials: MW
authors.lastname: Jackson
authors.affiliation: Invenio Therapeutics, Lexington, KY.|MirX Pharmaceuticals, Cleveland, OH.
authors.forename: Mukesh K
authors.initials: MK
authors.lastname: Agarwal
authors.affiliation: Invenio Therapeutics, Lexington, KY.|Department of Pathology, Case Western Reserve University and University Hospitals Case Medical Center, Cleveland, OH.|MirX Pharmaceuticals, Cleveland, OH.
authors.forename: David N
authors.initials: DN
authors.lastname: Wald
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D018797:Cell Cycle Proteins; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004249:DNA Damage; D055808:Drug Discovery; D006801:Humans; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011485:Protein Binding / Q000187:drug effects; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000037:antagonists & inhibitors / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; D018797:Cell Cycle Proteins; C482775:MDM4 protein, human; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; D016159:Tumor Suppressor Protein p53