Pharmaceutical Inhibition of Neddylation as Promising Treatments for Various Cancers

Author(s): Lina Yin, Yuanyuan Xue, Qiannan Shang, Haichao Zhu, Meihua Liu, Yingxiang Liu, Qingzhong Hu*

Journal Name: Current Topics in Medicinal Chemistry

Volume 19 , Issue 12 , 2019

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Graphical Abstract:


Background: Neddylation is an important post-translational modification of proteins, in which a NEDD8 (neural-precursor-cell-expressed developmentally down-regulated 8) is covalently introduced onto the substrate proteins to regulate their functions and homeostasis. As neddylation is frequently up-regulated in various cancers, its interference was proposed as a promising therapy of related diseases.

Objective: The recent advances in developing neddylation interfering agents were summarized to provide an overview of current achievements and perspectives for future development.

Methods: Reports on neddylation interfering agents were acquired from Pubmed as well as the EPO and websites, which were subsequently analyzed and summarized according to targets, chemical structures and biological activities.

Results: Neddylation as a sophisticated procedure comprises proteolytic processing of NEDD8 precursor, deploying conjugating enzymes E1 (NAE), E2 (UBE2M and UBE2F) and various E3, as well as translocating NEDD8 along these conjugating enzymes sequentially and finally to substrate proteins. Among these nodes, NAE, UBE2M and the interaction between UBE2M-DCN1 have been targeted by small molecules, metal complexes, peptides and RNAi. A NAE inhibitor pevonedistat (MLN4924) is currently under evaluation in clinical trials for the treatment of various cancers.

Conclusion: With multiple inhibitory approaches of neddylation being introduced, the development of neddylation interference as a novel cancer therapy is significantly boosted recently, although its efficacy and the best way to achieve that are still to be demonstrated in clinical trials.

Keywords: Neddylation, Inhibitor, NEDD8, NAE, UBE2M, Pevonedistat.

Enchev, R.I.; Schulman, B.A.; Peter, M. Protein neddylation: Beyond cullin-RING ligases. Nat. Rev. Mol. Cell Biol., 2015, 16(1), 30-44. []. [PMID: 25531226].
Rabut, G.; Peter, M. Function and regulation of protein neddylation. ‘Protein modifications: beyond the usual suspects’ review series. EMBO Rep., 2008, 9(10), 969-976. []. [PMID: 18802447].
Oved, S.; Mosesson, Y.; Zwang, Y.; Santonico, E.; Shtiegman, K.; Marmor, M.D.; Kochupurakkal, B.S.; Katz, M.; Lavi, S.; Cesareni, G.; Yarden, Y. Conjugation to Nedd8 instigates ubiquitylation and down-regulation of activated receptor tyrosine kinases. J. Biol. Chem., 2006, 281(31), 21640-21651. []. [PMID: 16735510].
Xu, J.; Li, L.; Yu, G.; Ying, W.; Gao, Q.; Zhang, W.; Li, X.; Ding, C.; Jiang, Y.; Wei, D.; Duan, S.; Lei, Q.; Li, P.; Shi, T.; Qian, X.; Qin, J.; Jia, L. The neddylation-cullin 2-RBX1 E3 ligase axis targets tumor suppressor RhoB for degradation in liver cancer. Mol. Cell. Proteomics, 2015, 14(3), 499-509. []. [PMID: 25540389].
El Motiam, A.; Vidal, S.; de la Cruz-Herrera, C.F.; Da Silva-Alvarez, S.; Baz-Martinez, M.; Seoane, R.; Vidal, A.; Rodriguez, M.S.; Xirodimas, D.P.; Carvalho, A.S.; Beck, H.C.; Matthiesen, R.; Collado, M.; Rivas, C. Interplay between sumoylation and neddylation regulates rpl11 localization and function. FASEB J., 2018. [].
Huang, G.; Kaufman, A.J.; Ramanathan, Y.; Singh, B. SCCRO (DCUN1D1) promotes nuclear translocation and assembly of the neddylation E3 complex. J. Biol. Chem., 2011, 286(12), 10297-10304. []. [PMID: 21247897].
Loftus, S.J.; Liu, G.; Carr, S.M.; Munro, S.; La Thangue, N.B. NEDDylation regulates E2F-1-dependent transcription. EMBO Rep., 2012, 13(9), 811-818. []. [PMID: 22836579].
Zou, J.; Ma, W.; Li, J.; Littlejohn, R.; Zhou, H.; Kim, I.M.; Fulton, D.J.R.; Chen, W.; Weintraub, N.L.; Zhou, J.; Su, H. Neddylation mediates ventricular chamber maturation through repression of Hippo signaling. Proc. Natl. Acad. Sci. USA, 2018, 115(17), E4101-E4110. []. [PMID: 29632206].
Harper, J.W. Neddylating the guardian; Mdm2 catalyzed conjugation of Nedd8 to p53. Cell, 2004, 118(1), 2-4. []. [PMID: 15242638].
Ma, T.; Chen, Y.; Zhang, F.; Yang, C.Y.; Wang, S.; Yu, X. RNF111-dependent neddylation activates DNA damage-induced ubiquitination. Mol. Cell, 2013, 49(5), 897-907. []. [PMID: 23394999].
Wu, J.T.; Lin, H.C.; Hu, Y.C.; Chien, C.T. Neddylation and deneddylation regulate Cul1 and Cul3 protein accumulation. Nat. Cell Biol., 2005, 7(10), 1014-1020. []. [PMID: 16127432].
Li, L.; Liu, B.; Dong, T.; Lee, H.W.; Yu, J.; Zheng, Y.; Gao, H.; Zhang, Y.; Chu, Y.; Liu, G.; Niu, W.; Zheng, S.; Jeong, L.S.; Jia, L. Neddylation pathway regulates the proliferation and survival of macrophages. Biochem. Biophys. Res. Commun., 2013, 432(3), 494-498. []. [PMID: 23416079].
Yao, W.T.; Wu, J.F.; Yu, G.Y.; Wang, R.; Wang, K.; Li, L.H.; Chen, P.; Jiang, Y.N.; Cheng, H.; Lee, H.W.; Yu, J.; Qi, H.; Yu, X.J.; Wang, P.; Chu, Y.W.; Yang, M.; Hua, Z.C.; Ying, H.Q.; Hoffman, R.M.; Jeong, L.S.; Jia, L.J. Suppression of tumor angiogenesis by targeting the protein neddylation pathway. Cell Death Dis., 2014, 5e1059 []. [PMID: 24525735].
Kandala, S.; Kim, I.M.; Su, H. Neddylation and deneddylation in cardiac biology. Am. J. Cardiovasc. Dis., 2014, 4(4), 140-158. [PMID: 25628956].
Mathewson, N.; Toubai, T.; Kapeles, S.; Sun, Y.; Oravecz-Wilson, K.; Tamaki, H.; Wang, Y.; Hou, G.; Sun, Y.; Reddy, P. Neddylation plays an important role in the regulation of murine and human dendritic cell function. Blood, 2013, 122(12), 2062-2073. []. [PMID: 23863900].
Hrecka, K.; Gierszewska, M.; Srivastava, S.; Kozaczkiewicz, L.; Swanson, S.K.; Florens, L.; Washburn, M.P.; Skowronski, J. Lentiviral Vpr usurps Cul4-DDB1[VprBP] E3 ubiquitin ligase to modulate cell cycle. Proc. Natl. Acad. Sci. USA, 2007, 104(28), 11778-11783. []. [PMID: 17609381].
Zubiete-Franco, I.; Fernández-Tussy, P.; Barbier-Torres, L.; Simon, J.; Fernández-Ramos, D.; Lopitz-Otsoa, F.; Gutiérrez-de Juan, V.; de Davalillo, S.L.; Duce, A.M.; Iruzubieta, P.; Taibo, D.; Crespo, J.; Caballeria, J.; Villa, E.; Aurrekoetxea, I.; Aspichueta, P.; Varela-Rey, M.; Lu, S.C.; Mato, J.M.; Beraza, N.; Delgado, T.C.; Martínez-Chantar, M.L. Deregulated neddylation in liver fibrosis. Hepatology, 2017, 65(2), 694-709. []. [PMID: 28035772].
Ehrentraut, S.F.; Colgan, S.P. Implications of protein post-translational modifications in IBD. Inflamm. Bowel Dis., 2012, 18(7), 1378-1388. []. [PMID: 22223542].
Nekorchuk, M.D.; Sharifi, H.J.; Furuya, A.K.; Jellinger, R.; de Noronha, C.M. HIV relies on neddylation for ubiquitin ligase-mediated functions. Retrovirology, 2013, 10, 138. []. [PMID: 24245672].
Liu, N.; Zhang, J.; Yang, X.; Jiao, T.; Zhao, X.; Li, W.; Zhu, J.; Yang, P.; Jin, J.; Peng, J.; Li, Z.; Ye, X. Hdm2 promotes neddylation of hepatitis b virus hbx to enhance its stability and function. J. Virol., 2017, 91(16), 91. []. [PMID: 28592528].
Chen, Y.; Neve, R.L.; Liu, H. Neddylation dysfunction in Alzheimer’s disease. J. Cell. Mol. Med., 2012, 16(11), 2583-2591. []. [PMID: 22805479].
Zhou, W.; Xu, J.; Li, H.; Xu, M.; Chen, Z.J.; Wei, W.; Pan, Z.; Sun, Y. Neddylation e2 ube2f promotes the survival of lung cancer cells by activating crl5 to degrade noxa via the k11 linkage. Clin. Cancer Res., 2017, 23(4), 1104-1116. []. [PMID: 27591266].
Fernández-Ramos, D.; Martínez-Chantar, M.L. NEDDylation in liver cancer: The regulation of the RNA binding protein Hu antigen R. Pancreatology, 2015, 15(4)(Suppl.), S49-S54. []. [PMID: 25841271].
Gao, F.; Cheng, J.; Shi, T.; Yeh, E.T. Neddylation of a breast cancer-associated protein recruits a class III histone deacetylase that represses NFkappaB-dependent transcription. Nat. Cell Biol., 2006, 8(10), 1171-1177. []. [PMID: 16998474].
Wang, X.; Li, L.; Liang, Y.; Li, C.; Zhao, H.; Ye, D.; Sun, M.; Jeong, L.S.; Feng, Y.; Fu, S.; Jia, L.; Guo, X. Targeting the neddylation pathway to suppress the growth of prostate cancer cells: Therapeutic implication for the men’s cancer. BioMed Res. Int., 2014, 2014974309 []. [PMID: 25093192].
Li, L.; Wang, M.; Yu, G.; Chen, P.; Li, H.; Wei, D.; Zhu, J.; Xie, L.; Jia, H.; Shi, J.; Li, C.; Yao, W.; Wang, Y.; Gao, Q.; Jeong, L.S.; Lee, H.W.; Yu, J.; Hu, F.; Mei, J.; Wang, P.; Chu, Y.; Qi, H.; Yang, M.; Dong, Z.; Sun, Y.; Hoffman, R.M.; Jia, L. Overactivated neddylation pathway as a therapeutic target in lung cancer. J. Natl. Cancer Inst., 2014, 106(6)dju083 []. [PMID: 24853380].
McMillin, D.W.; Jacobs, H.M.; Delmore, J.E.; Buon, L.; Hunter, Z.R.; Monrose, V.; Yu, J.; Smith, P.G.; Richardson, P.G.; Anderson, K.C.; Treon, S.P.; Kung, A.L.; Mitsiades, C.S. Molecular and cellular effects of NEDD8-activating enzyme inhibition in myeloma. Mol. Cancer Ther., 2012, 11(4), 942-951. []. [PMID: 22246439].
Yu, J.; Huang, W.L.; Xu, Q.G.; Zhang, L.; Sun, S.H.; Zhou, W.P.; Yang, F. Overactivated neddylation pathway in human hepatocellular carcinoma. Cancer Med., 2018. Epub ahead of print []. [PMID: 29846044].
Mansouri, S.; Zadeh, G. Neddylation in glioblastomas. Neuro-oncol., 2015, 17(10), 1305-1306. []. [PMID: 26395059].
Guihard, S.; Ramolu, L.; Macabre, C.; Wasylyk, B.; Noël, G.; Abecassis, J.; Jung, A.C. The NEDD8 conjugation pathway regulates p53 transcriptional activity and head and neck cancer cell sensitivity to ionizing radiation. Int. J. Oncol., 2012, 41(4), 1531-1540. []. [PMID: 22895816].
Yang, J.; Hamid, O.; Carvajal, R.D. The need for neddylation: A key to achieving ned in uveal melanoma. Clin. Cancer Res., 2018, 24(15), 3477-3479. []. [PMID: 29610291].
Pan, W.W.; Zhou, J.J.; Yu, C.; Xu, Y.; Guo, L.J.; Zhang, H.Y.; Zhou, D.; Song, F.Z.; Fan, H.Y. Ubiquitin E3 ligase CRL4(CDT2/ DCAF2) as a potential chemotherapeutic target for ovarian surface epithelial cancer. J. Biol. Chem., 2013, 288(41), 29680-29691. []. [PMID: 23995842].
McLarnon, A. Cancer: Mdm2-regulated stabilization of HuR by neddylation in HCC and colon cancer--a possible target for therapy. Nat. Rev. Gastroenterol. Hepatol., 2011, 9(1), 4. [PMID: 22158377].
Zhou, L.; Zhang, W.; Sun, Y.; Jia, L. Protein neddylation and its alterations in human cancers for targeted therapy. Cell. Signal., 2018, 44, 92-102. []. [PMID: 29331584].
Jiang, Y.; Jia, L. Neddylation pathway as a novel anti-cancer target: Mechanistic investigation and therapeutic implication. Anticancer. Agents Med. Chem., 2015, 15(9), 1127-1133. []. [PMID: 25742093].
Mo, Z.; Zhang, Q.; Liu, Z.; Lauer, J.; Shi, Y.; Sun, L.; Griffin, P.R.; Yang, X.L. Neddylation requires glycyl-tRNA synthetase to protect activated E2. Nat. Struct. Mol. Biol., 2016, 23(8), 730-737. []. [PMID: 27348078].
Huang, D.T.; Ayrault, O.; Hunt, H.W.; Taherbhoy, A.M.; Duda, D.M.; Scott, D.C.; Borg, L.A.; Neale, G.; Murray, P.J.; Roussel, M.F.; Schulman, B.A. E2-RING expansion of the NEDD8 cascade confers specificity to cullin modification. Mol. Cell, 2009, 33(4), 483-495. []. [PMID: 19250909].
Xirodimas, D.P.; Saville, M.K.; Bourdon, J.C.; Hay, R.T.; Lane, D.P. Mdm2-mediated NEDD8 conjugation of p53 inhibits its transcriptional activity. Cell, 2004, 118(1), 83-97. []. [PMID: 15242646].
Zuo, W.; Huang, F.; Chiang, Y.J.; Li, M.; Du, J.; Ding, Y.; Zhang, T.; Lee, H.W.; Jeong, L.S.; Chen, Y.; Deng, H.; Feng, X.H.; Luo, S.; Gao, C.; Chen, Y.G. c-Cbl-mediated neddylation antagonizes ubiquitination and degradation of the TGF-β type II receptor. Mol. Cell, 2013, 49(3), 499-510. []. [PMID: 23290524].
Broemer, M.; Tenev, T.; Rigbolt, K.T.; Hempel, S.; Blagoev, B.; Silke, J.; Ditzel, M.; Meier, P. Systematic in vivo RNAi analysis identifies IAPs as NEDD8-E3 ligases. Mol. Cell, 2010, 40(5), 810-822. []. [PMID: 21145488].
He, S.; Cao, Y.; Xie, P.; Dong, G.; Zhang, L. The nedd8 non-covalent binding region in the smurf hect domain is critical to its ubiquitn ligase function. Sci. Rep., 2017, 7, 41364. []. [PMID: 28169289].
Noguchi, K.; Okumura, F.; Takahashi, N.; Kataoka, A.; Kamiyama, T.; Todo, S.; Hatakeyama, S. TRIM40 promotes neddylation of IKKγ and is downregulated in gastrointestinal cancers. Carcinogenesis, 2011, 32(7), 995-1004. []. [PMID: 21474709].
Rabut, G.; Le Dez, G.; Verma, R.; Makhnevych, T.; Knebel, A.; Kurz, T.; Boone, C.; Deshaies, R.J.; Peter, M. The TFIIH subunit Tfb3 regulates cullin neddylation. Mol. Cell, 2011, 43(3), 488-495. []. [PMID: 21816351].
Kurz, T.; Chou, Y.C.; Willems, A.R.; Meyer-Schaller, N.; Hecht, M.L.; Tyers, M.; Peter, M.; Sicheri, F. Dcn1 functions as a scaffold-type E3 ligase for cullin neddylation. Mol. Cell, 2008, 29(1), 23-35. []. [PMID: 18206966].
Kamitani, T.; Kito, K.; Fukuda-Kamitani, T.; Yeh, E.T. Targeting of NEDD8 and its conjugates for proteasomal degradation by NUB1. J. Biol. Chem., 2001, 276(49), 46655-46660. []. [PMID: 11585840].
Shamay, M.; Greenway, M.; Liao, G.; Ambinder, R.F.; Hayward, S.D. De novo DNA methyltransferase DNMT3b interacts with NEDD8-modified proteins. J. Biol. Chem., 2010, 285(47), 36377-36386. []. [PMID: 20847044].
Cope, G.A.; Suh, G.S.; Aravind, L.; Schwarz, S.E.; Zipursky, S.L.; Koonin, E.V.; Deshaies, R.J. Role of predicted metalloprotease motif of Jab1/Csn5 in cleavage of Nedd8 from Cul1. Science, 2002, 298(5593), 608-611. []. [PMID: 12183637].
Gan-Erdene, T.; Nagamalleswari, K.; Yin, L.; Wu, K.; Pan, Z.Q.; Wilkinson, K.D. Identification and characterization of DEN1, a deneddylase of the ULP family. J. Biol. Chem., 2003, 278(31), 28892-28900. []. [PMID: 12759362].
Brownell, J.E.; Sintchak, M.D.; Gavin, J.M.; Liao, H.; Bruzzese, F.J.; Bump, N.J.; Soucy, T.A.; Milhollen, M.A.; Yang, X.; Burkhardt, A.L.; Ma, J.; Loke, H.K.; Lingaraj, T.; Wu, D.; Hamman, K.B.; Spelman, J.J.; Cullis, C.A.; Langston, S.P.; Vyskocil, S.; Sells, T.B.; Mallender, W.D.; Visiers, I.; Li, P.; Claiborne, C.F.; Rolfe, M.; Bolen, J.B.; Dick, L.R. Substrate-assisted inhibition of ubiquitin-like protein-activating enzymes: the NEDD8 E1 inhibitor MLN4924 forms a NEDD8-AMP mimetic in situ. Mol. Cell, 2010, 37(1), 102-111. []. [PMID: 20129059].
Soucy, T.A.; Smith, P.G.; Milhollen, M.A.; Berger, A.J.; Gavin, J.M.; Adhikari, S.; Brownell, J.E.; Burke, K.E.; Cardin, D.P.; Critchley, S.; Cullis, C.A.; Doucette, A.; Garnsey, J.J.; Gaulin, J.L.; Gershman, R.E.; Lublinsky, A.R.; McDonald, A.; Mizutani, H.; Narayanan, U.; Olhava, E.J.; Peluso, S.; Rezaei, M.; Sintchak, M.D.; Talreja, T.; Thomas, M.P.; Traore, T.; Vyskocil, S.; Weatherhead, G.S.; Yu, J.; Zhang, J.; Dick, L.R.; Claiborne, C.F.; Rolfe, M.; Bolen, J.B.; Langston, S.P. An inhibitor of NEDD8-activating enzyme as a new approach to treat cancer. Nature, 2009, 458(7239), 732-736. []. [PMID: 19360080].
Lukkarila, J.L.; da Silva, S.R.; Ali, M.; Shahani, V.M.; Xu, G.W.; Berman, J.; Roughton, A.; Dhe-Paganon, S.; Schimmer, A.D.; Gunning, P.T. Identification of nae inhibitors exhibiting potent activity in leukemia cells: Exploring the structural determinants of nae specificity. ACS Med. Chem. Lett., 2011, 2(8), 577-582. []. [PMID: 24900352].
Lin, J.J.; Milhollen, M.A.; Smith, P.G.; Narayanan, U.; Dutta, A. NEDD8-targeting drug MLN4924 elicits DNA rereplication by stabilizing Cdt1 in S phase, triggering checkpoint activation, apoptosis, and senescence in cancer cells. Cancer Res., 2010, 70(24), 10310-10320. []. [PMID: 21159650].
Wang, Y.; Luo, Z.; Pan, Y.; Wang, W.; Zhou, X.; Jeong, L.S.; Chu, Y.; Liu, J.; Jia, L. Targeting protein neddylation with an NEDD8-activating enzyme inhibitor MLN4924 induced apoptosis or senescence in human lymphoma cells. Cancer Biol. Ther., 2015, 16(3), 420-429. []. [PMID: 25782162].
Luo, Z.; Yu, G.; Lee, H.W.; Li, L.; Wang, L.; Yang, D.; Pan, Y.; Ding, C.; Qian, J.; Wu, L.; Chu, Y.; Yi, J.; Wang, X.; Sun, Y.; Jeong, L.S.; Liu, J.; Jia, L. The Nedd8-activating enzyme inhibitor MLN4924 induces autophagy and apoptosis to suppress liver cancer cell growth. Cancer Res., 2012, 72(13), 3360-3371. []. [PMID: 22562464].
Chen, P.; Hu, T.; Liang, Y.; Li, P.; Chen, X.; Zhang, J.; Ma, Y.; Hao, Q.; Wang, J.; Zhang, P.; Zhang, Y.; Zhao, H.; Yang, S.; Yu, J.; Jeong, L.S.; Qi, H.; Yang, M.; Hoffman, R.M.; Dong, Z.; Jia, L. Neddylation inhibition activates the extrinsic apoptosis pathway through atf4-chop-dr5 axis in human esophageal cancer cells. Clin. Cancer Res., 2016, 22(16), 4145-4157. []. [PMID: 26983464].
Jia, L.; Li, H.; Sun, Y. Induction of p21-dependent senescence by an NAE inhibitor, MLN4924, as a mechanism of growth suppression. Neoplasia, 2011, 13(6), 561-569. []. [PMID: 21677879].
Luo, Z.; Pan, Y.; Jeong, L.S.; Liu, J.; Jia, L. Inactivation of the Cullin (CUL)-RING E3 ligase by the NEDD8-activating enzyme inhibitor MLN4924 triggers protective autophagy in cancer cells. Autophagy, 2012, 8(11), 1677-1679. []. [PMID: 22874562].
Paiva, C.; Godbersen, J.C.; Berger, A.; Brown, J.R.; Danilov, A.V. Targeting neddylation induces DNA damage and checkpoint activation and sensitizes chronic lymphocytic leukemia B cells to alkylating agents. Cell Death Dis., 2015, 6, 1807. []. [PMID: 26158513].
Nawrocki, S.T.; Kelly, K.R.; Smith, P.G.; Keaton, M.; Carraway, H.; Sekeres, M.A.; Maciejewski, J.P.; Carew, J.S. The NEDD8-activating enzyme inhibitor MLN4924 disrupts nucleotide metabolism and augments the efficacy of cytarabine. Clin. Cancer Res., 2015, 21(2), 439-447. []. [PMID: 25388161].
Jazaeri, A.A.; Shibata, E.; Park, J.; Bryant, J.L.; Conaway, M.R.; Modesitt, S.C.; Smith, P.G.; Milhollen, M.A.; Berger, A.J.; Dutta, A. Overcoming platinum resistance in preclinical models of ovarian cancer using the neddylation inhibitor MLN4924. Mol. Cancer Ther., 2013, 12(10), 1958-1967. []. [PMID: 23939375].
Vanderdys, V.; Allak, A.; Guessous, F.; Benamar, M.; Read, P.W.; Jameson, M.J.; Abbas, T. The neddylation inhibitor pevonedistat (mln4924) suppresses and radiosensitizes head and neck squamous carcinoma cells and tumors. Mol. Cancer Ther., 2018, 17(2), 368-380. []. [PMID: 28838998].
Wei, D.; Li, H.; Yu, J.; Sebolt, J.T.; Zhao, L.; Lawrence, T.S.; Smith, P.G.; Morgan, M.A.; Sun, Y. Radiosensitization of human pancreatic cancer cells by MLN4924, an investigational NEDD8-activating enzyme inhibitor. Cancer Res., 2012, 72(1), 282-293. []. [PMID: 22072567].
Jin, Y.; Zhang, P.; Wang, Y.; Jin, B.; Zhou, J.; Zhang, J.; Pan, J. Neddylation blockade diminishes hepatic metastasis by dampening cancer stem-like cells and angiogenesis in uveal melanoma. Clin. Cancer Res., 2018, 24(15), 3741-3754. []. [PMID: 29233905].
Kuo, K.L.; Ho, I.L.; Shi, C.S.; Wu, J.T.; Lin, W.C.; Tsai, Y.C.; Chang, H.C.; Chou, C.T.; Hsu, C.H.; Hsieh, J.T.; Chang, S.C.; Pu, Y.S.; Huang, K.H. MLN4924, a novel protein neddylation inhibitor, suppresses proliferation and migration of human urothelial carcinoma: In vitro and in vivo studies. Cancer Lett., 2015, 363(2), 127-136. []. [PMID: 25615422].
Hua, W.; Li, C.; Yang, Z.; Li, L.; Jiang, Y.; Yu, G.; Zhu, W.; Liu, Z.; Duan, S.; Chu, Y.; Yang, M.; Zhang, Y.; Mao, Y.; Jia, L. Suppression of glioblastoma by targeting the overactivated protein neddylation pathway. Neuro-oncol., 2015, 17(10), 1333-1343. []. [PMID: 25904638].
Shah, J.J.; Jakubowiak, A.J.; O’Connor, O.A.; Orlowski, R.Z.; Harvey, R.D.; Smith, M.R.; Lebovic, D.; Diefenbach, C.; Kelly, K.; Hua, Z.; Berger, A.J.; Mulligan, G.; Faessel, H.M.; Tirrell, S.; Dezube, B.J.; Lonial, S. Phase i study of the novel investigational nedd8-activating enzyme inhibitor pevonedistat (mln4924) in patients with relapsed/refractory multiple myeloma or lymphoma. Clin. Cancer Res., 2016, 22(1), 34-43. []. [PMID: 26561559].
Swords, R.T.; Erba, H.P.; DeAngelo, D.J.; Bixby, D.L.; Altman, J.K.; Maris, M.; Hua, Z.; Blakemore, S.J.; Faessel, H.; Sedarati, F.; Dezube, B.J.; Giles, F.J.; Medeiros, B.C. Pevonedistat (MLN4924), a First-in-Class NEDD8-activating enzyme inhibitor, in patients with acute myeloid leukaemia and myelodysplastic syndromes: a phase 1 study. Br. J. Haematol., 2015, 169(4), 534-543. []. [PMID: 25733005].
Swords, R.T.; Watts, J.; Erba, H.P.; Altman, J.K.; Maris, M.; Anwer, F.; Hua, Z.; Stein, H.; Faessel, H.; Sedarati, F.; Dezube, B.J.; Giles, F.J.; Medeiros, B.C.; DeAngelo, D.J. Expanded safety analysis of pevonedistat, a first-in-class NEDD8-activating enzyme inhibitor, in patients with acute myeloid leukemia and myelodysplastic syndromes. Blood Cancer J., 2017, 7(2)e520 []. [PMID: 28157218].
Lockhart, A.C.; Bauer, T.M.; Aggarwal, C.; Lee, C.B.; Harvey, R.D.; Cohen, R.B.; Sedarati, F.; Nip, T.K.; Faessel, H.; Dash, A.B.; Dezube, B.J.; Faller, D.V.; Dowlati, A. Phase ib study of pevonedistat, a nedd8-activating enzyme inhibitor, in combination with docetaxel, carboplatin and paclitaxel, or gemcitabine, in patients with advanced solid tumors. Invest. New Drugs, 2018, 37(1), 87-97. []. [PMID: 29781056].
Sarantopoulos, J.; Shapiro, G.I.; Cohen, R.B.; Clark, J.W.; Kauh, J.S.; Weiss, G.J.; Cleary, J.M.; Mahalingam, D.; Pickard, M.D.; Faessel, H.M.; Berger, A.J.; Burke, K.; Mulligan, G.; Dezube, B.J.; Harvey, R.D. Phase i study of the investigational nedd8-activating enzyme inhibitor pevonedistat (tak-924/mln4924) in patients with advanced solid tumors. Clin. Cancer Res., 2016, 22(4), 847-857. []. [PMID: 26423795].
Bhatia, S.; Pavlick, A.C.; Boasberg, P.; Thompson, J.A.; Mulligan, G.; Pickard, M.D.; Faessel, H.; Dezube, B.J.; Hamid, O. A phase I study of the investigational NEDD8-activating enzyme inhibitor pevonedistat (TAK-924/MLN4924) in patients with metastatic melanoma. Invest. New Drugs, 2016, 34(4), 439-449. []. [PMID: 27056178].
a) Identifier: NCT02610777 An efficacy and safety study of pevonedistat plus azacitidine versus single-agent azacitidine in participants with higher-risk myelodysplastic syndromes (HR MDS), chronic myelomonocytic leukemia (CMML) and low-blast acute myelogenous leukemia (AML). Millennium Pharmaceuticals, Inc. 2016.(Available at:. ct2/show/NCT02610777#studydesc
(b) Identifier: NCT03228186, Trial of pevonedistat plus docetaxel in patients with previously treated advanced non-small cell lung cancer. University of Michigan Rogel Cancer Center, 2018.(Available at:. ct2/show/NCT03228186
(c)Michael, R. Identifier: NCT03238248, Pevonedistat and Azacitidine in MDS or MDS/MPN patients who fail primary therapy With DNA Methyl transferase inhibitors. Vanderbilt-Ingram Cancer Center 2017.(Available at:.
(d) Identifier: NCT03319537, Pevonedistat alone and in combination with chemotherapy in patients with mesothelioma. Memorial Sloan Kettering Cancer Center 2017.(Available at:.
(e) Identifier: NCT03330821, Pevonedistat, cytarabine, and idarubicin in treating patients with acute myeloid leukemia. University of Southern California 2018.(Available at:.
(f) Identifier: NCT03013998, Study of biomarker- based treatment of acute myeloid leukemia. Beat AML, LLC 2016.(Available at:.
[73] Identifier: NCT03268954, Pevonedistat plus azacitidine versus single-agent azacitidine as first-line treatment for participants with higher-risk myelodysplastic syndromes (hr mds), chronic myelomonocytic leukemia (cmml), or low-blast acute myelogenous leukemia (AML) (PANTHER). Millennium Pharmaceuticals, Inc. 2017.(Available at:. show/NCT03268954
An, H.; Statsyuk, A.V. An inhibitor of ubiquitin conjugation and aggresome formation. Chem. Sci. (Camb.), 2015, 6(9), 5235-5245. []. [PMID: 28717502].
Mizutani, T.; Yoshimura, C.; Kondo, H.; Kitade, M.; Ohkubo, S. Novel pyrrolopyrimidine compound or salt thereof, pharmaceutical composition containing same, especially agent for prevention and.or treatment of tumors etc based on NAE inhibitory effect. EP3103802 2016.
Leung, C.H.; Chan, D.S.; Yang, H.; Abagyan, R.; Lee, S.M.; Zhu, G.Y.; Fong, W.F.; Ma, D.L. A natural product-like inhibitor of NEDD8-activating enzyme. Chem. Commun. (Camb.), 2011, 47(9), 2511-2513. []. [PMID: 21240405].
Zhong, H.J.; Ma, V.P.; Cheng, Z.; Chan, D.S.; He, H.Z.; Leung, K.H.; Ma, D.L.; Leung, C.H. Discovery of a natural product inhibitor targeting protein neddylation by structure-based virtual screening. Biochimie, 2012, 94(11), 2457-2460. []. [PMID: 22709868].
Zhong, H.J.; Yang, H.; Chan, D.S.; Leung, C.H.; Wang, H.M.; Ma, D.L. A metal-based inhibitor of NEDD8-activating enzyme. PLoS One, 2012, 7(11)e49574 []. [PMID: 23185368].
Zhong, H.J.; Wang, W.; Kang, T.S.; Yan, H.; Yang, Y.; Xu, L.; Wang, Y.; Ma, D.L.; Leung, C.H. A rhodium(iii) complex as an inhibitor of neural precursor cell expressed, developmentally down-regulated 8-activating enzyme with in vivo activity against inflammatory bowel disease. J. Med. Chem., 2017, 60(1), 497-503. []. [PMID: 27976900].
Lu, P.; Liu, X.; Yuan, X.; He, M.; Wang, Y.; Zhang, Q.; Ouyang, P.K. Discovery of a novel nedd8 activating enzyme inhibitor with piperidin-4-amine scaffold by structure-based virtual screening. ACS Chem. Biol., 2016, 11(7), 1901-1907. []. [PMID: 27135934].
Lu, P.; Guo, Y.; Zhu, L.; Xia, Y.; Zhong, Y.; Wang, Y. A novel NAE/UAE dual inhibitor LP0040 blocks neddylation and ubiquitination leading to growth inhibition and apoptosis of cancer cells. Eur. J. Med. Chem., 2018, 154, 294-304. []. [PMID: 29843100].
Zhang, S.; Tan, J.; Lai, Z.; Li, Y.; Pang, J.; Xiao, J.; Huang, Z.; Zhang, Y.; Ji, H.; Lai, Y. Effective virtual screening strategy toward covalent ligands: identification of novel NEDD8-activating enzyme inhibitors. J. Chem. Inf. Model., 2014, 54(6), 1785-1797. []. [PMID: 24857708].
Ma, H.; Zhuang, C.; Xu, X.; Li, J.; Wang, J.; Min, X.; Zhang, W.; Zhang, H.; Miao, Z. Discovery of benzothiazole derivatives as novel non-sulfamide NEDD8 activating enzyme inhibitors by target-based virtual screening. Eur. J. Med. Chem., 2017, 133, 174-183. []. [PMID: 28388520].
Zhong, H.J.; Liu, L.J.; Chan, D.S.; Wang, H.M.; Chan, P.W.; Ma, D.L.; Leung, C.H. Structure-based repurposing of FDA-approved drugs as inhibitors of NEDD8-activating enzyme. Biochimie, 2014, 102, 211-215. []. [PMID: 24657219].
Wu, K.J.; Zhong, H.J.; Li, G.; Liu, C.; Wang, H.D.; Ma, D.L.; Leung, C.H. Structure-based identification of a NEDD8-activating enzyme inhibitor via drug repurposing. Eur. J. Med. Chem., 2018, 143, 1021-1027. []. [PMID: 29232579].
Scott, D.C.; Sviderskiy, V.O.; Monda, J.K.; Lydeard, J.R.; Cho, S.E.; Harper, J.W.; Schulman, B.A. Structure of a RING E3 trapped in action reveals ligation mechanism for the ubiquitin-like protein NEDD8. Cell, 2014, 157(7), 1671-1684. []. [PMID: 24949976].
Scott, D.C.; Hammill, J.T.; Min, J.; Rhee, D.Y.; Connelly, M.; Sviderskiy, V.O.; Bhasin, D.; Chen, Y.; Ong, S.S.; Chai, S.C.; Goktug, A.N.; Huang, G.; Monda, J.K.; Low, J.; Kim, H.S.; Paulo, J.A.; Cannon, J.R.; Shelat, A.A.; Chen, T.; Kelsall, I.R.; Alpi, A.F.; Pagala, V.; Wang, X.; Peng, J.; Singh, B.; Harper, J.W.; Schulman, B.A.; Guy, R.K. Blocking an N-terminal acetylation-dependent protein interaction inhibits an E3 ligase. Nat. Chem. Biol., 2017, 13(8), 850-857. []. [PMID: 28581483].
Hammill, J.T.; Scott, D.C.; Min, J.; Connelly, M.C.; Holbrook, G.; Zhu, F.; Matheny, A.; Yang, L.; Singh, B.; Schulman, B.A.; Guy, R.K. Piperidinyl ureas chemically control defective in cullin neddylation 1 (dcn1)-mediated cullin neddylation. J. Med. Chem., 2018, 61(7), 2680-2693. []. [PMID: 29547696].
Hammill, J.T.; Bhasin, D.; Scott, D.C.; Min, J.; Chen, Y.; Lu, Y.; Yang, L.; Kim, H.S.; Connelly, M.C.; Hammill, C.; Holbrook, G.; Jeffries, C.; Singh, B.; Schulman, B.A.; Guy, R.K. Discovery of an orally bioavailable inhibitor of defective in cullin neddylation 1 (dcn1)-mediated cullin neddylation. J. Med. Chem., 2018, 61(7), 2694-2706. []. [PMID: 29547693].
Zhou, H.; Lu, J.; Liu, L.; Bernard, D.; Yang, C.Y.; Fernandez-Salas, E.; Chinnaswamy, K.; Layton, S.; Stuckey, J.; Yu, Q.; Zhou, W.; Pan, Z.; Sun, Y.; Wang, S. A potent small-molecule inhibitor of the DCN1-UBC12 interaction that selectively blocks cullin 3 neddylation. Nat. Commun., 2017, 8(1), 1150. []. [PMID: 29074978].
Zhou, H.; Zhou, W.; Zhou, B.; Liu, L.; Chern, T.R.; Chinnaswamy, K.; Lu, J.; Bernard, D.; Yang, C.Y.; Li, S.; Wang, M.; Stuckey, J.; Sun, Y.; Wang, S. High-affinity peptidomimetic inhibitors of the dcn1-ubc12 protein-protein interaction. J. Med. Chem., 2018, 61(5), 1934-1950. []. [PMID: 29438612].
Richardson, K.S.; Zundel, W. The emerging role of the COP9 signalosome in cancer. Mol. Cancer Res., 2005, 3(12), 645-653. []. [PMID: 16380502].
Schlierf, A.; Altmann, E.; Quancard, J.; Jefferson, A.B.; Assenberg, R.; Renatus, M.; Jones, M.; Hassiepen, U.; Schaefer, M.; Kiffe, M.; Weiss, A.; Wiesmann, C.; Sedrani, R.; Eder, J.; Martoglio, B. Targeted inhibition of the COP9 signalosome for treatment of cancer. Nat. Commun., 2016, 7, 13166. []. [PMID: 27774986].

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Year: 2019
Published on: 29 July, 2019
Page: [1059 - 1069]
Pages: 11
DOI: 10.2174/1568026619666190311110646
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