Activity of TAS4464, a novel NEDD8 activating enzyme E1 inhibitor, against multiple myeloma via inactivation of nuclear factor κB pathways

Abstract

The ubiquitin proteasome pathway is essential for the proliferation and survival of multiple myeloma (MM) cells. TAS4464, a novel highly potent inhibitor of NEDD8 activating enzyme, selectively inactivates cullin-RING ubiquitin E3 ligases, resulting in accumulation of their substrates. Here, we examined 14 MM cell lines treated with TAS4464. TAS4464 induced growth arrest and cell death in the MM cell lines even in the presence of bone marrow stromal cells. It also induced the accumulation of phospho-inhibitor of κBα and phospho-p100, impaired the activities of nuclear factor κB (NF-κB) transcription factors p65 and RelB, and decreased the expression of NF-κB target genes, suggesting that TAS4464 inhibits both the canonical and noncanonical NF-κB pathways. TAS4464 had similar effects in an in vivo human-MM xenograft mouse model in which it was also observed to have strong antitumor effects. TAS4464 synergistically enhanced the antitumor activities of the standard MM chemotherapies bortezomib, lenalidomide/dexamethasone, daratumumab and elotuzumab. Together, these results suggest that the anti-MM activity of TAS4464 occurs via inhibition of the NF-κB pathways, and that treatment with TAS4464 is a potential approach for treating MM by single and combination therapies. K E Y W O R D S molecular targeted therapy, multiple myeloma, NEDD8 activating enzyme, nuclear factor κB, ubiquitin-like protein NEDD8 | 3803 MURAOKA et Al. most patients respond to those treatments initially, almost all patients who survive initial treatment eventually relapse and require further therapy. Therefore, more effective treatment options are urgently needed for the treatment of refractory MM.Nuclear factor κB (NF-κB) is constitutively activated in MM cells and is a trigger for the progression of MM. 3-6 NF-κB activity is controlled by canonical and non-canonical pathways. The NF-κB family of transcription factors comprises p65 (RelA), RelB, c-Rel, p50 (NF-κB1) and p52 (NF-κB2). These transcription factors form heterodimers such as p65-p50, which is involved in the canonical pathway, and p52-RelB, which is involved in the non-canonical pathway. 7 Although these dimers are constitutively present in the cytosol and nucleus, p65-p50 and p52-RelB are inactivated in the cytosol by inhibitor of κBα (IκBα) and p100-RelB, respec-

TAS4464, a NEDD8-activating enzyme inhibitor, activates both intrinsic and extrinsic apoptotic pathways via c-Myc-mediated regulation in acute myeloid leukemia

“…We previously reported the inhibitory effect of TAS4464 on the neddylation pathway in several hematopoietic cancers [ 27 , 31 ], and in this study, a similar drug functionality of TAS4464 was shown in AML cell lines by confirming the decrease in NEDD8 conjugation by Ubc12 or cullin1 (Fig. 3A ).…”

A first-in-human, phase 1 study of the NEDD8 activating enzyme E1 inhibitor TAS4464 in patients with advanced solid tumors

“…In preclinical analyses, the antiproliferative effects of TAS4464 increased in a dose- and time-dependent manner, plateauing after 24 h. Additionally, TAS4464 demonstrated promising antitumor effects in several hematologic and solid tumor xenograft models without notable weight loss [ 13 ]. Further, in vitro and in vivo investigations of TAS4464 in multiple myeloma models found that the antitumor activity of TAS4464 occurs through inhibition of nuclear factor κB (NFκB) activation, thereby affecting the canonical and noncanonical NFκB pathways [ 14 ].…”

Targeting NEDDylation as a Novel Approach to Improve the Treatment of Head and Neck Cancer

“…TAS yielded significantly reduced tumor burden in the THP-1 xenograft model of AML as well as a patient derived xenograft (PDX) model of small cell lung cancer [64,65]. TAS has also been reported to display significant antitumor activity in a xenograft model of multiple myeloma (MM) when combined with various standard of care agents [66]. Together, these results demonstrate the potential of TAS for therapeutic use in a wide variety of cancer types.…”