Chemical genetics screen for enhancers of rapamycin identifies a specific inhibitor of an SCF family E3 ubiquitin ligase

Aghajan, Mariam; Jonai, Nao; Flick, Karin; Fu, Fei; Luo, Manlin; Cai, Xiaona; Ouni, Ikram; Pierce, Nathan W.; Tang, Xiaobo; Lomenick, Brett; Damoiseaux, Robert; Hao, Rui; Moral, Pierre Del; Verma, Rati; Liu, Ying; Li, Cheng; Houk, K. N.; Jung, Michael E.; Zheng, Ning; Huang, Lan; Deshaies, Raymond J.; Kaiser, Peter; Huang, Jing

doi:10.1038/nbt.1645

Cited by 127 publications

(139 citation statements)

References 41 publications

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“…One example is SMER3, detected from a screen for potentiators of the antiproliferative drug rapamycin. SMER3 potently blocks the F-box protein Met30 to prevent degradation of Met4, an antiproliferative transcriptional activator (44). Another small molecule screening approach revealed the compound SCF-I2, which allosterically blocks activity of the yeast F-box protein Cdc4, but not its human ortholog FBXW7 (45).…”

Section: Therapeuticsmentioning

confidence: 99%

Emerging therapies targeting the ubiquitin proteasome system in cancer

Weathington¹,

Mallampalli²

2014

J. Clin. Invest.

112

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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Section: Therapeuticsmentioning

confidence: 99%

Emerging therapies targeting the ubiquitin proteasome system in cancer

Weathington¹,

Mallampalli²

2014

J. Clin. Invest.

112

104

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“…The first gene product identified was Met30p, which influenced the import of PS into mitochondria. MET30 encodes a subunit of a multicomponent E3 ubiquitin ligase (Aghajan et al 2010;Ouni et al 2010) and affects substrate specificity of the ubiquitin ligase (Chandrasekaran et al 2006;Yan and Xiong 2010). One substrate for the E3 ubiquitin ligase is the transcription factor Met4p, which is inactivated upon ubiquitination.…”

Section: Transport Of Phospholipids Between the Endoplasmic Reticulummentioning

confidence: 99%

Lipid Transport between the Endoplasmic Reticulum and Mitochondria

Flis

Daum

2013

Cold Spring Harbor Perspectives in Biology

171

127

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Mitochondria are partially autonomous organelles that depend on the import of certain proteins and lipids to maintain cell survival and membrane formation. Although phosphatidylglycerol, cardiolipin, and phosphatidylethanolamine are synthesized by mitochondrial enzymes, phosphatidylcholine, phosphatidylinositol, phosphatidylserine, and sterols need to be imported from other organelles. The origin of most lipids imported into mitochondria is the endoplasmic reticulum, which requires interaction of these two subcellular compartments. Recently, protein complexes that are involved in membrane contact between endoplasmic reticulum and mitochondria were identified, but their role in lipid transport is still unclear. In the present review, we describe components involved in lipid translocation between the endoplasmic reticulum and mitochondria and discuss functional as well as regulatory aspects that are important for lipid homeostasis.

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“…When one is considering effective therapy with rapalogs and other anticancer agents, the concept of synthetic lethality may help overcome many of the problems described above (24,25). We envision that these agents may be used in combination therapy with rapamycin to yield the following benefits: to sensitize a tumor's response to rapamycin, to provide a synthetic lethal strategy against rapamycin-insensitive tumors, and to prevent or delay the development of rapamycin resistance in tumors (analogous to the successful use of drug cocktails for treating HIV infection).…”

Section: Mtor Inhibitors In Clinical Trials and The Need For Companiomentioning

confidence: 99%