Pevonedistat

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Pevonedistat
Pevonedistat.svg
Identifiers
  • [(1S,2S,4R)-4-[4-[ [(1S)-2,3-dihydro-1H-inden-1-yl]amino]pyrrolo[2,3-d]pyrimidin-7-yl]-2-hydroxycyclopentyl]methyl sulfamate
CAS Number
PubChem CID
DrugBank
ChEMBL
Chemical and physical data
Formula C21H25N5O4S
Molar mass 443.52 g·mol−1
3D model (JSmol)
  • C1CC2=CC=CC=C2[C@H]1NC3=C4C=CN(C4=NC=N3)[C@@H]5C[C@H]([C@H](C5)O)COS(=O)(=O)N
  • InChI=1S/C21H25N5O4S/c22-31(28,29)30-11-14-9-15(10-19(14)27)26-8-7-17-20(23-12-24-21(17)26)25-18-6-5-13-3-1-2-4-16(13)18/h1-4,7-8,12,14-15,18-19,27H,5-6,9-11H2,(H2,22,28,29)(H,23,24,25)/t14-,15+,18-,19-/m0/s1
  • Key:MPUQHZXIXSTTDU-QXGSTGNESA-N

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

Contents

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 genome instability in 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 demonstrated 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]

Related Research Articles

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<span class="mw-page-title-main">UBA1</span> Protein-coding gene in the species Homo sapiens

Ubiquitin-like modifier activating enzyme 1 (UBA1) is an enzyme which in humans is encoded by the UBA1 gene. UBA1 participates in ubiquitination and the NEDD8 pathway for protein folding and degradation, among many other biological processes. This protein has been linked to X-linked spinal muscular atrophy type 2, neurodegenerative diseases, and cancers.

<span class="mw-page-title-main">Deubiquitinating enzyme</span>

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<span class="mw-page-title-main">NEDD8</span>

NEDD8 is a protein that in humans is encoded by the NEDD8 gene. This ubiquitin-like (UBL) protein becomes covalently conjugated to a limited number of cellular proteins, in a process called NEDDylation similar to ubiquitination. Human NEDD8 shares 60% amino acid sequence identity to ubiquitin. The primary known substrates of NEDD8 modification are the cullin subunits of cullin-based E3 ubiquitin ligases, which are active only when NEDDylated. Their NEDDylation is critical for the recruitment of E2 to the ligase complex, thus facilitating ubiquitin conjugation. NEDD8 modification has therefore been implicated in cell cycle progression and cytoskeletal regulation.

<span class="mw-page-title-main">APPBP1</span> Protein-coding gene in the species Homo sapiens

NEDD8-activating enzyme E1 regulatory subunit is a protein that in humans is encoded by the NAE1 gene.

<span class="mw-page-title-main">UBE1C</span> Protein-coding gene in the species Homo sapiens

NEDD8-activating enzyme E1 catalytic subunit is a protein that in humans is encoded by the UBA3 gene.

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References

  1. 1 2 Czuczman NM, Barth MJ, Gu J, Neppalli V, Mavis C, Frys SE, et al. (March 2016). "Pevonedistat, a NEDD8-activating enzyme inhibitor, is active in mantle cell lymphoma and enhances rituximab activity in vivo". Blood. 127 (9): 1128–1137. doi:10.1182/blood-2015-04-640920. PMC   4778163 . PMID   26675347.
  2. 1 2 3 Xu GW, Toth JI, da Silva SR, Paiva SL, Lukkarila JL, Hurren R, et al. (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. CC-BY icon.svg Material was copied from this source, which is available under a Creative Commons Attribution 4.0 International (CC BY 4.0) license.
  3. Wolenski FS, Fisher CD, Sano T, Wyllie SD, Cicia LA, Gallacher MJ, 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.
  4. Soucy TA, Smith PG, Milhollen MA, Berger AJ, Gavin JM, Adhikari S, et al. (April 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.
  5. Jin B, Robertson KD (2013). "DNA Methyltransferases, DNA Damage Repair, and Cancer". Epigenetic Alterations in Oncogenesis. Advances in Experimental Medicine and Biology. Vol. 754. pp. 3–29. doi:10.1007/978-1-4419-9967-2_1. ISBN   978-1-4419-9966-5. PMC   3707278 . PMID   22956494.
  6. Swords RT, Erba HP, DeAngelo DJ, Bixby DL, Altman JK, Maris M, et al. (May 2015). "Pevonedistat (MLN4924), a First-in-Class NEDD8-activating enzyme inhibitor, in patients with acute myeloid leukaemia and myelodysplastic syndromes: a phase 1 study". British Journal of Haematology. 169 (4): 534–543. doi: 10.1111/bjh.13323 . hdl: 2027.42/111220 . PMID   25733005.
  7. Shah JJ, Jakubowiak AJ, O'Connor OA, Orlowski RZ, Harvey RD, Smith MR, et al. (January 2016). "Phase I Study of the Novel Investigational NEDD8-Activating Enzyme Inhibitor Pevonedistat (MLN4924) in Patients with Relapsed/Refractory Multiple Myeloma or Lymphoma". Clinical Cancer Research. 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, et al. (August 2016). "A phase I study of the investigational NEDD8-activating enzyme inhibitor pevonedistat (TAK-924/MLN4924) in patients with metastatic melanoma". Investigational New Drugs. 34 (4): 439–449. doi:10.1007/s10637-016-0348-5. PMC   4919369 . PMID   27056178.
  9. Sarantopoulos J, Shapiro GI, Cohen RB, Clark JW, Kauh JS, Weiss GJ, et al. (February 2016). "Phase I Study of the Investigational NEDD8-Activating Enzyme Inhibitor Pevonedistat (TAK-924/MLN4924) in Patients with Advanced Solid Tumors". Clinical Cancer Research. 22 (4): 847–857. doi: 10.1158/1078-0432.CCR-15-1338 . PMID   26423795.

Further reading