A Small-Molecule Inhibitor of MDMX Activates p53 and Induces Apoptosis

Wang, Hongbo; Ma, Xujun; Ren, Shumei; Buolamwini, John K.; Yan, Chunhong

doi:10.1158/1535-7163.mct-10-0581

Cited by 111 publications

(111 citation statements)

References 52 publications

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“…The role of inactivation of wild-type p53 resulting from up-regulation of MDM2 (and/or MDM4) has recently been explored. [28][29][30][31]42,43 Our data confirmed that MDM2 protein levels are higher to various degrees in PV CD34 ϩ cells than that in normal CD34 ϩ cells. Additional studies will be required to determine whether MDM2 levels can be used to predict in vitro or in vivo responses to IFN-␣ and nutlin treatment.…”

Section: Discussionsupporting

confidence: 63%

Combination treatment in vitro with Nutlin, a small-molecule antagonist of MDM2, and pegylated interferon-α 2a specifically targets JAK2V617F-positive polycythemia vera cells

Lü

Wang

et al. 2012

Blood

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Section: Discussionsupporting

confidence: 63%

Combination treatment in vitro with Nutlin, a small-molecule antagonist of MDM2, and pegylated interferon-α 2a specifically targets JAK2V617F-positive polycythemia vera cells

Lü

Wang

et al. 2012

Blood

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“…Agents suppressing the interaction of p53 with these E3 ligases result in accumulation of p53, triggering apoptotic cancer cell death, making them prime drug design candidates (34). Many compounds, including serdemetan, nutlin-3 (RO5045337), and NSC-207895 all demonstrate in vitro anticancer activity (35)(36)(37). Serdemetan was tested in a phase I trial, with p53 induction seen, but cardiac conduction defects were observed (38).…”

Section: Therapeuticsmentioning

confidence: 99%

Emerging therapies targeting the ubiquitin proteasome system in cancer

Weathington¹,

Mallampalli²

2014

J. Clin. Invest.

111

104

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The ubiquitin proteasome system (UPS) is an essential metabolic constituent of cellular physiology that tightly regulates cellular protein concentrations with specificity and precision to optimize cellular function. Inhibition of the proteasome has proven very effective in the treatment of multiple myeloma, and this approach is being tested for utility in other malignancies. New pharmaceuticals targeting the proteasome itself or specific proximal pathways of the UPS are in development as antiproliferatives or immunomodulatory agents. In this article, we discuss the biology of UPS-targeting drugs, their use as therapy for neoplasia, and the state of clinical and preclinical development for emerging therapeutics. IntroductionA new era in myeloma therapy. At the turn of the millennium, targeted molecular therapeutics against hematologic malignancies initiated a shift in our perspective on treatment, prognosis, and survival for patients with some of the most aggressive and fatal neoplasms. Bortezomib (branded and marketed as Velcade by Millennium Pharmaceuticals) entered the armamentarium of new antiproliferative therapies with approval in May 2003 for the hematologic malignancy multiple myeloma (MM), in which B cellderived plasma cells clonally proliferate and produce large quantities of monoclonal antibody. MM can be a devastating disease, with renal failure, blood hyperviscosity, and bone marrow invasion seen clinically. Before 2000, there were few life-prolonging therapies for the disease. Bortezomib blocks the proteolytic activity of the 26S proteasome, a cellular structure whose role in cell metabolism has now been meticulously characterized; indeed, bortezomib is the first agent available for use in humans that inhibits the activity of this system. Bortezomib quickly proved effective in refractory MM (1), and its inclusion in initial MM treatment was superior to the conventional cytotoxic chemotherapy regimen alone (2).During this time thalidomide, an agent that produced deformities in infants of mothers prescribed the drug during pregnancy, further suppressed myeloma plasma cell proliferation when added to the regimen. A decade of careful clinical trials since these first breakthrough observations has revealed that therapeutic combinations including bortezomib with thalidomide or related compounds (collectively called immunomodulatory drugs, or IMiDs) and steroids confer a very favorable prognosis compared with historic therapy, greatly prolonging the median survival time from diagnosis over this period (3). When this therapy is implemented in conjunction with autologous bone marrow stem cell transplant, recent clinical trials show a three-year progression-free survival of 60% and overall survival of 90% for patients eligible for stem cell transplant (4), compared with only 48% three-year relative survival for patients diagnosed in 1999 (5). Multiple clinical trials for this new generation of MM molecular therapies are underway, with median survival projected by some to exceed 10 years in the post-bortezomib...

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“…XI-100 blocks MdmX transcription and acts synergistically with nutlin in cancer cell lines overexpressing MdmX [44].…”

Section: Targeting Mdmxmentioning

confidence: 99%

Wild type p53 reactivation: From lab bench to clinic

Selivanova

2014

FEBS Letters

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Keywords: p53 Small molecule Mdm2 MdmX Apoptosis ROS a b s t r a c tThe p53 tumor suppressor is the most frequently inactivated gene in cancer. Several mouse models have demonstrated that the reconstitution of the p53 function suppresses the growth of established tumors. These facts, taken together, promote the idea of p53 reactivation as a strategy to combat cancer. This review will focus on recent advances in the development of small molecules which restore the function of wild type p53 by blocking its inhibitors Mdm2 and MdmX or their upstream regulators and discuss the impact of different p53 functions for tumor prevention and tumor eradication. Finally, the recent progress in p53 research will be analyzed concerning the role of p53 cofactors and cellular environment in the biological response upon p53 reactivation and how this can be applied in clinic.

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A Small-Molecule Inhibitor of MDMX Activates p53 and Induces Apoptosis

Cited by 111 publications

References 52 publications

Combination treatment in vitro with Nutlin, a small-molecule antagonist of MDM2, and pegylated interferon-α 2a specifically targets JAK2V617F-positive polycythemia vera cells

Combination treatment in vitro with Nutlin, a small-molecule antagonist of MDM2, and pegylated interferon-α 2a specifically targets JAK2V617F-positive polycythemia vera cells

Emerging therapies targeting the ubiquitin proteasome system in cancer

Wild type p53 reactivation: From lab bench to clinic

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