Pevonedistat

Pevonedistat (MLN4924) is a selective NEDD8 inhibitor.[1] It is being investigated as a cancer treatment, e.g. for mantle cell lymphoma (MCL).[1]

Target of pevonedistat

NEDD8-activating enzyme (NAE) is a heterodimeric molecule consisting of amyloid beta precursor protein-binding protein 1 (APPBP1) and ubiquitin-like modifier activating enzyme 3 (UBA3).[2] As reviewed by Xu et al., in a first step NAE binds ATP and NEDD8 and catalyzes the formation of a NEDD8-AMP intermediate. This intermediate binds the adenylation domain of NAE. NEDD8-AMP reacts with the catalytic cysteine in UBA3 during which NEDD8 is transferred to the catalytic cysteine, resulting in a high energy thioester linkage. NAE then binds ATP and NEDD8 to generate a second NEDD8-AMP, forming a fully loaded NAE carrying two activated NEDD8 molecules (i.e., one as a thioester and the other as an adenylate).[2]

Pevonedistat is an AMP mimetic. Pevonedistat forms a stable covalent adduct with NEDD8 in the NAE catalytic pocket of UBA3 by reacting with thioester-linked NEDD8 bound to the enzyme's catalytic cysteine. Unlike the labile NEDD8-AMP intermediate, the NEDD8-pevonedistat adduct cannot be utilized in subsequent reactions necessary for NAE activity.[2]

Mechanism of action

"Inhibition of NAE prevents activation of cullin-RING ligases (CRLs), which are critical for proteasome-mediated protein degradation."[3] MLN4924 has been shown to disrupt CRL-mediated protein turnover leading to apoptosis in cancer cells by deregulating S-phase DNA synthesis.[4] Essentially it encourages apoptosis in dividing cells.

In addition to proteasome-mediated protein degradation, activated NEDD8 is needed for at least two pathways of DNA repair, nucleotide excision repair (NER) and non-homologous end joining (NHEJ) (see NEDD8).

One or more DNA repair genes in seven DNA repair pathways are frequently epigenetically silenced in cancers (see e.g. DNA repair pathways).[5]) This is a likely source of the genome instability of cancers. If activation of NEDD8 is inhibited by pevonedistat, cells will then have an additional induced deficiency of NER or NHEJ. Such cells may then die because of deficient DNA repair leading to accumulation of DNA damages. The effect of NEDD8 inhibition may be greater for cancer cells than for normal cells if the cancer cells are already deficient in DNA repair due to prior epigenetic silencing of DNA repair genes active in alternative pathways (see synthetic lethality).

Clinical trials

In a phase 1 trial to determine dosing in patients with AML and myelodysplastic syndromes "modest clinical activity was observed".[6]

More recently, in 2016, pevonedistat has shown a significant therapeutic effect in three further Phase I clinical cancer trials. These include pevonedistat trials against relapsed/refractory multiple myeloma or lymphoma,[7] metastatic melanoma,[8] and advanced solid tumors.[9]

References
  1. Czuczman et al. (2015). "Pevonedistat, a NEDD8 activating enzyme inhibitor, is active in mantle cell lymphoma and enhances rituximab activity in vivo". Blood. 127 (9): 1128–37. doi:10.1182/blood-2015-04-640920. PMC 4778163. PMID 26675347.CS1 maint: uses authors parameter (link)
  2. Xu GW, Toth JI, da Silva SR, Paiva SL, Lukkarila JL, Hurren R, Maclean N, Sukhai MA, Bhattacharjee RN, Goard CA, Medeiros B, Gunning PT, Dhe-Paganon S, Petroski MD, Schimmer AD (2014). "Mutations in UBA3 confer resistance to the NEDD8-activating enzyme inhibitor MLN4924 in human leukemic cells". PLOS ONE. 9 (4): e93530. Bibcode:2014PLoSO...993530X. doi:10.1371/journal.pone.0093530. PMC 3972249. PMID 24691136. Material was copied from this source, which is available under a Creative Commons Attribution 4.0 International (CC BY 4.0) license.
  3. Wolenski et al. (2015). "The NAE inhibitor pevonedistat (MLN4924) synergizes with TNF-α to activate apoptosis". Cell Death Discovery. 1: 15034. doi:10.1038/cddiscovery.2015.34. PMC 4979425. PMID 27551465.CS1 maint: uses authors parameter (link)
  4. Soucy, T.A., Smith, P.G., Milhollen, M.A. et al. (2009). "An inhibitor of NEDD8-activating enzyme as a new approach to treat cancer". Nature. 458 (7239): 732–736. Bibcode:2009Natur.458..732S. doi:10.1038/nature07884. PMID 19360080. S2CID 41289859.CS1 maint: uses authors parameter (link)
  5. Jin B, Robertson KD (2013). "DNA methyltransferases, DNA damage repair, and cancer". Adv. Exp. Med. Biol. Advances in Experimental Medicine and Biology. 754: 3–29. doi:10.1007/978-1-4419-9967-2_1. ISBN 978-1-4419-9966-5. PMC 3707278. PMID 22956494.
  6. Swords et al. (2015). "Pevonedistat (MLN4924), a First-in-Class NEDD8-activating enzyme inhibitor, in patients with acute myeloid leukaemia and myelodysplastic syndromes: a phase 1 study" (PDF). Br J Haematol. 169 (4): 534–43. doi:10.1111/bjh.13323. hdl:2027.42/111220. PMID 25733005.CS1 maint: uses authors parameter (link)
  7. Shah JJ, Jakubowiak AJ, O'Connor OA, Orlowski RZ, Harvey RD, Smith MR, Lebovic D, Diefenbach C, Kelly K, Hua Z, Berger AJ, Mulligan G, Faessel HM, Tirrell S, Dezube BJ, Lonial S (2016). "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. 22 (1): 34–43. doi:10.1158/1078-0432.CCR-15-1237. PMC 5694347. PMID 26561559.
  8. Bhatia S, Pavlick AC, Boasberg P, Thompson JA, Mulligan G, Pickard MD, Faessel H, Dezube BJ, Hamid O (2016). "A phase I study of the investigational NEDD8-activating enzyme inhibitor pevonedistat (TAK-924/MLN4924) in patients with metastatic melanoma". Invest New Drugs. 34 (4): 439–49. doi:10.1007/s10637-016-0348-5. PMC 4919369. PMID 27056178.
  9. Sarantopoulos J, Shapiro GI, Cohen RB, Clark JW, Kauh JS, Weiss GJ, Cleary JM, Mahalingam D, Pickard MD, Faessel HM, Berger AJ, Burke K, Mulligan G, Dezube BJ, Harvey RD (2016). "Phase I Study of the Investigational NEDD8-Activating Enzyme Inhibitor Pevonedistat (TAK-924/MLN4924) in Patients with Advanced Solid Tumors". Clin. Cancer Res. 22 (4): 847–57. doi:10.1158/1078-0432.CCR-15-1338. PMID 26423795.

Further reading
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