Leucettamol A: A new inhibitor of Ubc13-Uev1A interaction isolated from a marine sponge, Leucetta aff. microrhaphis

Tsukamoto, Sachiko; Takeuchi, Tomoharu; Rotinsulu, Henki; Mangindaan, Remy E.P.; Soest, R.W.M. van; Ukai, Kazuyo; Kobayashi, Haruo; Namikoshi, Michio; Ohta, Tomihisa; Yokosawa, Hideyoshi

doi:10.1016/j.bmcl.2008.10.110

Cited by 73 publications

(55 citation statements)

References 17 publications

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“…25,26 Given the in vivo function of Ubc13, the potential of targeting this E2 enzyme has been proposed, and several compounds that inhibited the complex formation between Ubc13 and Uev1A have been described previously. 27,28 The utility of these compounds for the development of therapeutics, however, has been questioned because of their chemical properties. 29 Chronic active BCR signaling, 11 together with MYD88-medated signaling, 13 is largely responsible for the constitutive NF-B activity in ABC-DLBCL cells and controls the proliferation and survival of these cells.…”

Section: Introductionmentioning

confidence: 99%

Inhibition of proliferation and survival of diffuse large B-cell lymphoma cells by a small-molecule inhibitor of the ubiquitin-conjugating enzyme Ubc13-Uev1A

Pulvino¹,

Ye²,

Oleksyn

et al. 2012

Blood

127

119

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IntroductionDiffuse large B-cell lymphoma (DLBCL) is an aggressive and heterogeneous disease comprising at least 3 major subtypes with distinct molecular, biologic, and clinical properties: activated B cell-like DLBCL (ABC-DLBCL), germinal center B cell-like DLBCL (GCB-DLBCL), and primary mediastinal B-cell lymphoma. 1,2 Although the overall cure rate for DLBCL reaches more than 50% with the current therapies such as R-CHOP (rituximab plus cyclophosphamide, hydroxydaunorubicin, oncovin, and prednisone/prednisolone), less than 40% of ABC-DLBCL patients are cured. [2][3][4] Therefore, new therapy approaches efficient for this and other DLBCL subtypes are highly desirable.The transcription factor NF-B controls the expression of a wide range of genes involved in cell proliferation, survival, stress response, angiogenesis, and inflammation. 5,6 NF-B activity is tightly regulated by multiple signaling pathways, and abnormal NF-B activation has been linked to cancer development and progression. [7][8][9] Constitutive NF-B activation has been observed in high frequency in all of the main DLBCL subtypes, especially in ABC-DLBCL, with more than 90% of the tumors showing nuclear NF-B, the hallmark of its activation. 9-14 A recent genomic study revealed that more than 60% of ABC-DLBCLs and approximately 30% of GCB-DLBCLs harbor somatic mutations in multiple components of NF-B signaling pathways, such as the BCR, CD40, and TLR pathways. 15 Significantly, it has been demonstrated that constitutive NF-B signaling is required for the proliferation and survival of ABC-DLBCL cell lines. 11,13,16,17 All of these observations suggest a primary role for constitutive NF-B signaling in the pathogenesis of DLBCL and, therefore, the NF-B signaling pathway may represent a rational therapeutic target in DLBCL. 9,11,18 Ubiquitination, the covalent attachment of the ubiquitin (Ub) molecule to target proteins, regulates diverse cellular processes. 19 Ubiquitination proceeds through a stepwise enzymatic cascade involving 3 classes of enzymes: a Ub-activating enzyme (E1), a Ub-conjugating enzyme (E2), and a Ub ligase (E3). The E1 enzyme activates Ub in an ATP-dependent manner and transfers the activated Ub to an E2 enzyme through the formation of a thioester bond between the carboxy terminus of Ub and the active site cysteine of the E2, generating an E2 and Ub thioester conjugate (referred to as E2ϳUb). The E2 then cooperates with an E3 to attach the Ub to a lysine residue of a substrate. Ub itself can serve as a substrate and the process can undergo multiple rounds, resulting in the formation of polyubiquitin chains. 19,20 Because Ub has 7 lysine residues and any one of them can be conjugated to another Ub, polyubiquitin chains of different linkages with distinct functional properties are formed in cells. For example, lysine 48 (K48)-linked polyubiquitin chains typically target substrates for proteasomal degradation, whereas K63-linked polyubiquitin chains function as scaffolds to assemble protein complexes in NF-B signaling and DNA repair. [...

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Section: Introductionmentioning

confidence: 99%

Inhibition of proliferation and survival of diffuse large B-cell lymphoma cells by a small-molecule inhibitor of the ubiquitin-conjugating enzyme Ubc13-Uev1A

Pulvino¹,

Ye²,

Oleksyn

et al. 2012

Blood

127

119

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“…Leucettamol A, which was isolated from the sea sponge Leucetta aff. Microrhaphis, was shown to inhibit the Ubc13-Uev1A interaction, blocking the E1-E2 complex formation [52]. It was determined that, contrary to an earlier assessment that this was a racemic compound, it is in fact a chiral and optically active compound [53].…”

Section: Targeting E2 Enzymesmentioning

confidence: 72%

Targeting Ubiquitination for Cancer Therapies

Morrow¹,

Lin

Sun

et al. 2015

Future Med. Chem.

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Ubiquitination, the structured degradation and turnover of cellular proteins, is regulated by the ubiquitin-proteasome system. Most proteins that are critical for cellular regulations and functions are targets of the process. Ubiquitination is comprised of a sequence of three enzymatic steps, and aberrations in the pathway can lead to tumor development and progression as observed in many cancer types. Recent evidence indicates that targeting the ubiquitin-proteasome system is effective for certain cancer treatment, but many more potential targets might have been previously overlooked. In this review, we will discuss the current state of small molecules that target various elements of ubiquitination. Special attention will be given to novel inhibitors of E3 ubiquitin ligases, especially those in the SCF family.Ubiquitination, a step in the nonlysosomal degradation of proteins, is a crucial post-translational modification in eukaryotic organisms. Rapid and timely degradation of transcriptional regulators and other proteins by the ubiquitin-proteasome system (UPS) regulates a wide variety of cellular processes [1]. Ubiquitination involves covalent attachment of ubiquitin, a small 8-kDa protein, to a substrate and results in recognition and shuttling of the substrate to the 26S proteasome complex for degradation [2]. It is important to note that the ubiquitination process combined with the proteasome complex step is also referred to as the ubiquitin-proteasome system (UPS) or ubiquitin proteasome pathway (UPP).The ubiquitination process is tightly controlled by three families of enzymes: ubiquitin-activating enzymes (E1s), ubiquitin-conjugating enzymes (E2s), and finally ubiquitin-protein enzymes (E3s). There exists two E1 enzymes with ubiquitin-activating capability: UBA1 being the primary E1 and the recently discovered UBA6 with unclear functions and uncharacterized regulations [3,4]. In contrast to the small number of E1s, there are approximately 40 E2s [5,6] and 500-1000 human E3 ligases, providing both specificity and versatility [7]. The three steps of the ubiquitination process (Figure 1) have been reviewed previously [8,9]. Briefly, the activation step requires binding of both ATP and ubiquitin and links the α-carboxyl group of the C-terminal glycine residue of ubiquitin to a cysteine residue on E1, and a thioester linkage is formed between the u biquitin and E1.Then the E2 binds to both activated ubiquitin and the E1 enzyme and thus transfers the ubiquitin from E1 to the active site cysteine of the E2 via a trans(thio)esterification reaction. Finally, the E3 catalyzes the linking of ubiquitin to a lysine residue on the substrate. Repetitions of these sequential steps results in a long chains of ubiquitin (polyubiquitin) on the protein to be degraded, and the specific lysine residue on ubiquitin used for linking (e.g., K48, K63, etc.) results in different topologies [10]. Ubiquitination was originally described as a mechanism by which cells dispose of short-lived, damaged, or abnormal proteins, but more rece...

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“…7) as a ubiquitin E1-specific inhibitor (IC 50 value, 50 µM). 29) In the course of the continuing search for E1 inhibitors, we next isolated five new alkaloids, hyrtioreticulines A-E 30) (35)(36)(37)(38)(39), together with one known alkaloid, hyrtioerectine B (40) (Fig. 7).…”

Section: Inhibitors Of E1mentioning

confidence: 99%

“…34) Since the knockdown of Ubc13 was previously reported to increase p53 transcriptional activity, 35) we speculated that an inhibitor of the Ubc13-Uev1A interaction may induce the activation of p53 transcriptional activity and function as an anticancer agent. In our screening, 36) inhibition of the Ubc13-Uev1A interaction was tested in enzyme-linked immunosorbent assay (ELISA) using purified recombinant Ubc13 and FLAG-Uev1A proteins and a primary anti-FLAG antibody.…”

Section: Inhibitors Of E2mentioning

confidence: 99%

Search for Inhibitors of the Ubiquitin–Proteasome System from Natural Sources for Cancer Therapy

Tsukamoto

2016

CHEMICAL & PHARMACEUTICAL BULLETIN

Self Cite

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Since the approval of the proteasome inhibitor, Velcade ® , by the Food and Drug Administration (FDA) for the treatment of relapsed multiple myeloma, inhibitors of the ubiquitin-proteasome system have been attracting increasing attention as promising drug leads for cancer therapy. While the development of drugs for diseases related to this proteolytic system has mainly been achieved by searching libraries of synthetic small molecules or chemical modifications to drug leads, limited searches have been conducted on natural sources. We have been searching natural sources for inhibitors that target this proteolytic system through in-house screening. Our recent studies on the search for natural inhibitors of the ubiquitin-proteasome system, particularly, inhibitors against the proteasome, E1 enzyme (Uba1), E2 enzyme (Ubc13-Uev1A heterodimer), and E3 enzyme (Hdm2), and also those against deubiquitinating enzyme (USP7), are reviewed here.

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Leucettamol A: A new inhibitor of Ubc13-Uev1A interaction isolated from a marine sponge, Leucetta aff. microrhaphis

Cited by 73 publications

References 17 publications

Inhibition of proliferation and survival of diffuse large B-cell lymphoma cells by a small-molecule inhibitor of the ubiquitin-conjugating enzyme Ubc13-Uev1A

Inhibition of proliferation and survival of diffuse large B-cell lymphoma cells by a small-molecule inhibitor of the ubiquitin-conjugating enzyme Ubc13-Uev1A

Targeting Ubiquitination for Cancer Therapies

Search for Inhibitors of the Ubiquitin–Proteasome System from Natural Sources for Cancer Therapy

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