SCH529074, a Small Molecule Activator of Mutant p53, Which Binds p53 DNA Binding Domain (DBD), Restores Growth-suppressive Function to Mutant p53 and Interrupts HDM2-mediated Ubiquitination of Wild Type p53

Demma, Mark; Maxwell, Eugene; Ramos, Robert; Liang, Lianzhu; Li, Cheng; Hesk, David; Rossman, Randall; Mallams, Alan K.; Doll, Ronald J.; Liu, Ming; Seidel-Dugan, Cynthia; Bishop, W. Robert; Dasmahapatra, Bimalendu

doi:10.1074/jbc.m109.083469

Cited by 91 publications

(73 citation statements)

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“…These include CDB3 (42), SCH529074 (43), CP-3139 (44), and PRIMA-1 MET /Apr-246 (45). At least some of them seem to inhibit the p53/MDM2 interaction via induction of a conformational change (43), although in most cases the mechanism remains elusive and awaits a detailed investigation.…”

Section: Discussionmentioning

confidence: 99%

Dual Targeting of Wild-Type and Mutant p53 by Small Molecule RITA Results in the Inhibition of N-Myc and Key Survival Oncogenes and Kills Neuroblastoma Cells In Vivo and In Vitro

Burmakin

Shi

Hedström

et al. 2013

Clinical Cancer Research

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Purpose: Restoration of the p53 function in tumors is a promising therapeutic strategy due to the high potential of p53 as tumor suppressor and the fact that established tumors depend on p53 inactivation for their survival. Here, we addressed the question whether small molecule RITA can reactivate p53 in neuroblastoma and suppress the growth of neuroblastoma cells in vitro and in vivo.Experimental Design: The ability of RITA to inhibit growth and to induce apoptosis was shown in seven neuroblastoma cell lines. Mechanistic studies were carried out to determine the p53 dependence and the molecular mechanism of RITA-induced apoptosis in neuroblastoma, using cell viability assays, RNAi silencing, co-immunoprecipitation, qPCR, and Western blotting analysis. In vivo experiments were conducted to study the effect of RITA on human neuroblastoma xenografts in mice.Results: RITA induced p53-dependent apoptosis in a set of seven neuroblastoma cell lines, carrying wild-type or mutant p53; it activated p53 and triggered the expression of proapoptotic p53 target genes. Importantly, p53 activated by RITA inhibited several key oncogenes that are high-priority targets for pharmacologic anticancer strategies in neuroblastoma, including N-Myc, Aurora kinase, Mcl-1, Bcl-2, Wip-1, MDM2, and MDMX. Moreover, RITA had a strong antitumor effect in vivo.Conclusions: Reactivation of wild-type and mutant p53 resulting in the induction of proapoptotic factors along with ablation of key oncogenes by compounds such as RITA may be a highly effective strategy to treat neuroblastoma.

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Section: Discussionmentioning

confidence: 99%

Dual Targeting of Wild-Type and Mutant p53 by Small Molecule RITA Results in the Inhibition of N-Myc and Key Survival Oncogenes and Kills Neuroblastoma Cells In Vivo and In Vitro

Burmakin

Shi

Hedström

et al. 2013

Clinical Cancer Research

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“…The small molecule SCH529074 was shown to bind to the core domain of p53 and act as a chaperone that restores wild type function [41]. In addition, it inhibits p53 ubiquitination by Mdm2.…”

Section: Small Molecules That Target Mutant P53mentioning

confidence: 99%

Mutant p53 reactivation by small molecules makes its way to the clinic

2014

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The TP53 tumor suppressor gene is mutated in many human tumors, including common types of cancer such as colon and ovarian cancer. This illustrates the key role of p53 as trigger of cell cycle arrest or cell death upon oncogenic stress. Most TP53 mutations are missense mutations that result in single amino acid substitutions in p53 and expression of high levels of dysfunctional p53 protein. Restoration of wild type p53 function in such tumor cells will induce robust cell death and allow efficient eradication of the tumor. Therapeutic targeting of mutant p53 in tumors is a rapidly developing field at the forefront of translational cancer research. Various approaches have led to the identification of small molecules that can rescue mutant p53. These include compounds that target specific p53 mutations, including PK083 and PK5174 (Y220C mutant p53) and NSC319726 (R175H mutant p53), as well as PRIMA‐1 and its analog APR‐246 that affect a wider range of mutant p53 proteins. APR‐246 has been tested in a Phase I/II clinical trial with promising results.

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“…Some mutations adversely affect the stability of the core domain of p53 119 yet are still expressed or even overexpressed; for this subset of mutants, compounds that stabilize the native protein conformation appear to restore its tumor suppressor activity. 120,121 Such compounds have not yet advanced beyond preclinical studies. A third intriguing approach to targeting mutant p53 involves abrogating the G2 checkpoint of the cell cycle in the presence of traditional cytotoxic chemotherapeutics that cause DNA damage; because loss of p53 M Monographs activity abolishes the G1 checkpoint, treatment with G2 checkpoint inhibitors forces the tumor cells into mitosis with irreparable DNA damage.…”

Section: Tp53mentioning

confidence: 99%

The Genomics of Lung Adenocarcinoma: Opportunities for Targeted Therapies

Greulich

2010

Genes & Cancer

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Standard cytotoxic chemotherapy is effective for some cancers, but for many others, available treatments offer only a limited survival benefit. Lung adenocarcinoma is one such cancer, responsible for approximately half of lung cancer deaths each year. Development of targeted therapies is thought to hold the most promise for successfully treating this disease, but a targeted approach is dependent on understanding the genomic state of the tumor cells. Exon-directed sequencing of large numbers of lung adenocarcinoma tumor samples has provided an initial low-resolution image of the somatic mutation profile of these tumors. Such cancer sequencing studies have confirmed the high frequency of TP53 and KRAS mutations in lung adenocarcinoma, have found inactivating mutations in known tumor suppressor genes not previously associated with lung adenocarcinoma, and have identified oncogenic mutations of EGFR upon which the first targeted therapy for lung adenocarcinoma patients was based. Additional candidate oncogenes await functional validation. It is anticipated that upcoming whole-exome and whole-genome lung adenocarcinoma sequencing experiments will reveal a more detailed landscape of somatic mutations that can be exploited for therapeutic purposes.

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SCH529074, a Small Molecule Activator of Mutant p53, Which Binds p53 DNA Binding Domain (DBD), Restores Growth-suppressive Function to Mutant p53 and Interrupts HDM2-mediated Ubiquitination of Wild Type p53

Cited by 91 publications

References 50 publications

Dual Targeting of Wild-Type and Mutant p53 by Small Molecule RITA Results in the Inhibition of N-Myc and Key Survival Oncogenes and Kills Neuroblastoma Cells In Vivo and In Vitro

Dual Targeting of Wild-Type and Mutant p53 by Small Molecule RITA Results in the Inhibition of N-Myc and Key Survival Oncogenes and Kills Neuroblastoma Cells In Vivo and In Vitro

Mutant p53 reactivation by small molecules makes its way to the clinic

The Genomics of Lung Adenocarcinoma: Opportunities for Targeted Therapies

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