A small-molecule inhibitor of the ubiquitin activating enzyme for cancer treatment

Hyer, Marc L.; Milhollen, Michael A.; Ciavarri, Jeff; Fleming, Paul; Traore, Tary; Sappal, Darshan S.; Huck, Jessica J.; Shi, Judy; Gavin, James M.; Brownell, Jim; Yang, Yu; Stringer, Bradley; Griffin, Robert J.; Bruzzese, Frank J.; Soucy, Teresa A.; Duffy, Jennifer; Rabino, Claudia; Riceberg, Jessica; Hoar, Kara M.; Lublinsky, Anya; Menon, Saurabh; Sintchak, Michael D.; Bump, Nancy J.; Pulukuri, Sai Murali Krishna; Langston, Steve; Tirrell, Stephen; Kuranda, Mike; Veiby, Petter; Newcomb, John; Li, Ping; Wu, Jing; Je, Powe; Dick, Lawrence R.; Greenspan, Paul D.; Galvin, Katherine; Manfredi, Mark; Claiborne, Chris; Amidon, Benjamin S.; Bence, Neil

doi:10.1038/nm.4474

Cited by 270 publications

(301 citation statements)

References 42 publications

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“…Additionally, pre-treatment of AML cells with TAK-243 reduced their ability to resolve DSBs as evidenced by sustained γH2AX foci. A prior study showed that TAK-243 synergized with radiation in patient-derived breast and non-small cell lung cancer cells in vivo [9]. …”

mentioning

confidence: 99%

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The ubiquitin-activating enzyme, UBA1, as a novel therapeutic target for AML

Barghout¹,

Schimmer²

2018

Oncotarget

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confidence: 99%

“…characterized the mode of action and biological activity of TAK-243 in cell-free and cell-based systems and evaluated the preclinical efficacy in several mouse models of solid (prostate, ovarian, breast, colon, neck and lung) and hematologic (multiple myeloma and lymphoma) malignancies, further demonstrating efficacy and tolerability of this drug [9]. …”

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confidence: 99%

The ubiquitin-activating enzyme, UBA1, as a novel therapeutic target for AML

Barghout¹,

Schimmer²

2018

Oncotarget

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“…The ubiquitin-proteasome system (UPS) represents the main mechanism of protein degradation and the regulation of every step within this mechanism is crucial to prevent several disorders and diseases such as tumor development and progression. A recent example of an existing drug that targets the ubiquitin system is the adenosine sulfamate inhibitor, TAK-243, which inhibits the ubiquitin activation enzyme (E1) (UAE/UBA1) (Hyer et al, 2018). TAK-243 has entered phase I trial studies for the treatment of patients with relapsed or refractory acute myeloid leukemia, refractory myelodysplastic syndrome or chronic myelomonocytic leukemia (NCT03816319).…”

Section: Principal Strategies To Regulate the Isg15 Conjugation Systemmentioning

confidence: 99%

Strategies to Target ISG15 and USP18 Toward Therapeutic Applications

2020

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The interferon (IFN)-stimulated gene product 15 (ISG15) represents an ubiquitin-like protein (Ubl), which in a process termed ISGylation can be covalently linked to target substrates via a cascade of E1, E2, and E3 enzymes. Furthermore, ISG15 exerts functions in its free form both, as an intracellular and as a secreted protein. In agreement with its role as a type I IFN effector, most functions of ISG15 and ISGylation are linked to the anti-pathogenic response. However, also key roles in other cellular processes such as protein translation, cytoskeleton dynamics, exosome secretion, autophagy or genome stability and cancer were described. Ubiquitin-specific protease 18 (USP18) constitutes the major ISG15 specific protease which counteracts ISG15 conjugation. Remarkably, USP18 also functions as a critical negative regulator of the IFN response irrespective of its enzymatic activity. Concordantly, lack of USP18 function causes fatal interferonopathies in humans and mice. The negative regulatory function of USP18 in IFN signaling is regulated by various protein-protein interactions and its stability is controlled via proteasomal degradation. The broad repertoire of physiological functions and regulation of ISG15 and USP18 offers a variety of potential intervention strategies which might be of therapeutic use. Due to the high mutation rates of pathogens which are often species specific and constantly give rise to a variety of immune evasion mechanisms, immune effector systems are under constant evolutionarily pressure. Therefore, it is not surprising that considerable differences in ISG15 with respect to function and sequence exist even among closely related species. Hence, it is essential to thoroughly evaluate the translational potential of results obtained in model organisms especially for therapeutic strategies. This review covers existing and conceptual assay systems to target and identify modulators of ISG15, ISGylation, USP18 function, and protein-protein interactions within this context. Strategies comprise mouse models for translational perspectives, cell-based and biochemical assays as well as chemical probes.

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“…Whilst there has been considerable interest in targeting the proteasome with newly identified drugs [15], until recently [16,17] ubiquitin biology has been largely neglected in malaria research. There is extensive current research to identify inhibitors of the ubiquitin pathway for other therapeutic applications, particularly in the area of cancer chemotherapy [18]. One class of E1 inhibitor is the adenosyl sulphamates that form a covalent adduct with ubiquitin.…”

Section: Introductionmentioning

confidence: 99%

“…This reaction is catalysed by E1 and inhibits further ATP-based activation of ubiquitin. MLN7243 (TAK-243) is one of these compounds; it inhibits the human (Homo sapiens) and yeast (Saccharomyces cerevisiae) ubiquitin E1 (HsUBA1 and ScUBA1) and structural data have been obtained for E1 with bound inhibitor and bound ubiquitin [18][19][20]. However, it is unknown whether MLN7243 inhibits P. falciparum (Pf) UBA1.…”

Section: Introductionmentioning

confidence: 99%

Protein ubiquitylation is essential for the schizont to merozoite transition in Plasmodium falciparum blood-stage development

Encheva

Green

Lasonder

et al. 2019

Preprint

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Ubiquitylation is a common post translational modification of eukaryotic proteins and in the human malaria parasite, Plasmodium falciparum (Pf) overall ubiquitylation increases in the transition from intracellular schizont to extracellular merozoite stages in the asexual blood stage cycle. Here, we identify specific ubiquitylation sites of protein substrates in three intracellular parasite stages and extracellular merozoites; a total of 1464 sites in 546 proteins were identified (data available via ProteomeXchange with identifier PXD014998). 469 ubiquitylated proteins were identified in merozoites compared with only 160 in the preceding intracellular schizont stage, indicating a large increase in protein ubiquitylation associated with merozoite maturation. Following merozoite invasion of erythrocytes, few ubiquitylated proteins were detected in the first intracellular ring stage but as parasites matured through trophozoite to schizont stages the extent of ubiquitylation increased. We identified commonly used ubiquitylation motifs and groups of ubiquitylated proteins in specific areas of cellular function, for example merozoite pellicle proteins involved in erythrocyte invasion, exported proteins, and histones. To investigate the importance of ubiquitylation we screened ubiquitin pathway inhibitors in a parasite growth assay and identified the ubiquitin activating enzyme (UBA1 or E1) inhibitor MLN7243 (TAK-243) to be particularly effective. This small molecule was shown to be a potent inhibitor of recombinant PfUBA1, and a structural homology model of MLN7243 bound to the parasite enzyme highlights avenues for the development of P. falciparum specific inhibitors. We created a genetically modified parasite with a rapamycin-inducible functional deletion of uba1; addition of either MLN7243 or rapamycin to the recombinant parasite line resulted in the same phenotype, with parasite development blocked at the late schizont stage.These results indicate that the intracellular target of MLN7243 is UBA1, and this activity is essential for the final differentiation of schizonts to merozoites. The ubiquitylation of many merozoite proteins and their disappearance in ring stages are consistent with the idea that ubiquitylation leads to their destruction via the proteasome once their function is complete following invasion, which would allow amino acid recycling in the period prior to the parasite's elaboration of a new food vacuole.

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A small-molecule inhibitor of the ubiquitin activating enzyme for cancer treatment

Cited by 270 publications

References 42 publications

The ubiquitin-activating enzyme, UBA1, as a novel therapeutic target for AML

The ubiquitin-activating enzyme, UBA1, as a novel therapeutic target for AML

Strategies to Target ISG15 and USP18 Toward Therapeutic Applications

Protein ubiquitylation is essential for the schizont to merozoite transition in Plasmodium falciparum blood-stage development

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