The clinical development of an inhibitor of cellular proteasome function suggests that compounds targeting other components of the ubiquitin-proteasome system might prove useful for the treatment of human malignancies. NEDD8-activating enzyme (NAE) is an essential component of the NEDD8 conjugation pathway that controls the activity of the cullin-RING subtype of ubiquitin ligases, thereby regulating the turnover of a subset of proteins upstream of the proteasome. Substrates of cullin-RING ligases have important roles in cellular processes associated with cancer cell growth and survival pathways. Here we describe MLN4924, a potent and selective inhibitor of NAE. MLN4924 disrupts cullin-RING ligase-mediated protein turnover leading to apoptotic death in human tumour cells by a new mechanism of action, the deregulation of S-phase DNA synthesis. MLN4924 suppressed the growth of human tumour xenografts in mice at compound exposures that were well tolerated. Our data suggest that NAE inhibitors may hold promise for the treatment of cancer.
The proteasome was validated as an oncology target following the clinical success of VELCADE (bortezomib) for injection for the treatment of multiple myeloma and recurring mantle cell lymphoma. Consequently, several groups are pursuing the development of additional small-molecule proteasome inhibitors for both hematologic and solid tumor indications. Here, we describe MLN9708, a selective, orally bioavailable, secondgeneration proteasome inhibitor that is in phase I clinical development. MLN9708 has a shorter proteasome dissociation half-life and improved pharmacokinetics, pharmacodynamics, and antitumor activity compared with bortezomib. MLN9708 has a larger blood volume distribution at steady state, and analysis of 20S proteasome inhibition and markers of the unfolded protein response confirmed that MLN9708 has greater pharmacodynamic effects in tissues than bortezomib. MLN9708 showed activity in both solid tumor and hematologic preclinical xenograft models, and we found a correlation between greater pharmacodynamic responses and improved antitumor activity. Moreover, antitumor activity was shown via multiple dosing routes, including oral gavage. Taken together, these data support the clinical development of MLN9708 for both hematologic and solid tumor indications. Cancer Res; 70(5); 1970-80. ©2010 AACR.
IntroductionMLN4924 is a potent and selective small-molecule inhibitor of NEDD8-activating enzyme (NAE) that is currently in phase 1 clinical trials. 1-3 NAE plays an essential role in regulating the activity of a subset of ubiquitin E3 ligases, the cullin-RING ligases (CRLs), which are responsible for regulating destruction of many intracellular proteins. 4 NAE activates the small ubiquitin-like molecule NEDD8 as the first step in the neddylation cascade. 5 NAE hydrolyzes adenosine triphosphate (ATP) to adenylate NEDD8 at its C-terminus and transfers NEDD8 from the adenyl group to a specific cysteine within NAE. The activated NEDD8 is then transferred to the active-site cysteine of Ubc12 or UBE2F the E2s specific for the NEDD8 pathway. Finally, NEDD8 is conjugated on a conserved lysine near the C-terminal end of a cullin protein; this covalent modification is required for the cullin complex to recruit a ubiquitin-charged E2 protein facilitating polyubiquitination of proteins, targeting them for proteasomal degradation. Thus, NAE plays a key role in regulating the levels (and therefore the function) of a subset of proteins.Many of the proteins that are substrates for CRL-mediated polyubiquitination have key roles in cell-cycle progression and signal transduction, making NAE inhibition an attractive target for anticancer therapy. MLN4924 potently inhibits NAE in vitro, resulting in inhibition of CRL neddylation and an increase in levels of CRL substrate proteins (eg, Cdt-1, Nrf-2). 3 The primary mechanism of action of NAE inhibition in many cell types is induction of DNA rereplication because of blocking degradation of Cdt-1, a critical factor required for licensing origins of DNA replication. 3 Dysregulation of Cdt-1 activity leads to DNA rereplication. 6,7 For example, overexpression of Cdt-1 and Cdc6 induces DNA rereplication, activates DNA damage repair pathways, and induces cell death. 7 Induction of DNA rereplication by MLN4924 results in S-phase accumulation, DNA-damage responses, and cell death 3 (M.A.M., U.N., T.A.S., P. Veiby, P.G.S., B. Amidon, manuscript in preparation). Similar effects were observed in human tumor xenografts where MLN4924 inhibited NAE in vivo leading to tumor growth inhibition. 3 The nuclear factor-B (NF-B) signaling pathway plays a key role in many aspects of cancer initiation and progression through transcriptional control of genes involved in growth, angiogenesis, antiapoptosis, invasiveness, and metastasis. 8 Regulation of NF-B signaling occurs at many levels, one of which is through the regulation of protein turnover by the action of CRLs. Under normal conditions, NF-B transcription factors are maintained in an inactive state by binding to IB proteins. In canonical NF-B signaling, IB␣ binds to p50-p65, sequesters the transcription factors in the cytoplasm rendering them inactive. On stimulation of the IKK complex, IB␣ is phosphorylated at Ser32 and Ser36, resulting in its polyubiquitination and degradation, 9-11 thus resulting in nuclear accumulation of the complex and transcri...
Background Histone lactylation, a metabolic stress-related histone modification, plays an important role in the regulation of gene expression during M1 macrophage polarization. However, the role of histone lactylation in tumorigenesis remains unclear. Results Here, we show histone lactylation is elevated in tumors and is associated with poor prognosis of ocular melanoma. Target correction of aberrant histone lactylation triggers therapeutic efficacy both in vitro and in vivo. Mechanistically, histone lactylation contributes to tumorigenesis by facilitating YTHDF2 expression. Moreover, YTHDF2 recognizes the m6A modified PER1 and TP53 mRNAs and promotes their degradation, which accelerates tumorigenesis of ocular melanoma. Conclusion We reveal the oncogenic role of histone lactylation, thereby providing novel therapeutic targets for ocular melanoma therapy. We also bridge histone modifications with RNA modifications, which provides novel understanding of epigenetic regulation in tumorigenesis.
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