Pevonedistat (MLN4924) is a selective

NEDD8 NEDD8 is a protein that in humans is encoded by the ''NEDD8'' gene. (in ''saccharomyces cerevisiae'' this protein is known as Rub1) This ubiquitin-like (UBL) protein becomes covalently conjugated to a limited number of cellular proteins, in a proc ...

inhibitor. It is being investigated as a cancer treatment, e.g. for

mantle cell lymphoma Mantle cell lymphoma (MCL) is a type of non-Hodgkin's lymphoma (NHL), comprising about 6% of NHL cases. There are only about 15,000 patients presently in the United States with mantle cell lymphoma. It is named for the mantle zone of the lymph n ...

(MCL).

Target of pevonedistat

NEDD8-activating enzyme (NAE) is a heterodimeric molecule consisting of amyloid beta precursor protein-binding protein 1 (

APPBP1 NEDD8-activating enzyme E1 regulatory subunit is a protein that in humans is encoded by the ''NAE1'' gene. Function The protein encoded by this gene binds to the beta-amyloid precursor protein. Beta-amyloid precursor protein is a cell surface ...

) and ubiquitin-like modifier activating enzyme 3 ( UBA3). CC-BY icon

Material was copied from this source, which is available under
Creative Commons Attribution 4.0 International (CC BY 4.0)
license. As reviewed by Xu et al., in a first step NAE binds ATP and NEDD8 and catalyzes the formation of a NEDD8-

AMP #REDIRECT Amp {{Redirect category shell, {{R from other capitalisation{{R from ambiguous page ...

intermediate. This intermediate binds the

adenylation Adenylylation, more commonly known as AMPylation, is a process in which an adenosine monophosphate (AMP) molecule is covalently attached to the amino acid side chain of a protein. This covalent addition of AMP to a hydroxyl side chain of the prote ...

domain of NAE. NEDD8-AMP reacts with the catalytic

cysteine Cysteine (symbol Cys or C; ) is a semiessential proteinogenic amino acid with the formula . The thiol side chain in cysteine often participates in enzymatic reactions as a nucleophile. When present as a deprotonated catalytic residue, sometime ...

in UBA3 during which NEDD8 is transferred to the catalytic cysteine, resulting in a high energy

thioester In organic chemistry, thioesters are organosulfur compounds with the functional group . They are analogous to carboxylate esters () with the sulfur in the thioester playing the role of the linking oxygen in the carboxylate ester, as implied by t ...

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). Pevonedistat is an AMP mimetic. Pevonedistat forms a stable covalent

adduct An adduct (from the Latin ''adductus'', "drawn toward" alternatively, a contraction of "addition product") is a product of a direct addition of two or more distinct molecules, resulting in a single reaction product containing all atoms of all co ...

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.

Mechanism of action

"Inhibition of NAE prevents activation of cullin-RING ligases (CRLs), which are critical for proteasome-mediated protein degradation." MLN4924 has been shown to disrupt CRL-mediated protein turnover leading to

apoptosis Apoptosis (from grc, ἀπόπτωσις, apóptōsis, 'falling off') is a form of programmed cell death that occurs in multicellular organisms. Biochemical events lead to characteristic cell changes (morphology) and death. These changes incl ...

in cancer cells by deregulating S-phase DNA synthesis. 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

). One or more DNA repair genes in seven DNA repair pathways are frequently

epigenetically In biology, epigenetics is the study of stable phenotypic changes (known as ''marks'') that do not involve alterations in the DNA sequence. The Greek prefix '' epi-'' ( "over, outside of, around") in ''epigenetics'' implies features that are "o ...

silenced in cancers (see e.g. DNA repair pathways).) This is a likely source of

genome instability Genome instability (also genetic instability or genomic instability) refers to a high frequency of mutations within the genome of a cellular lineage. These mutations can include changes in nucleic acid sequences, chromosomal rearrangements or aneup ...

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 Synthetic lethality is defined as a type of genetic interaction where the combination of two genetic events results in cell death or death of an organism. Although the foregoing explanation is wider than this, it is common when referring to synthet ...

Clinical trials

In a phase 1 trial to determine dosing in patients with AML and

myelodysplastic syndrome A myelodysplastic syndrome (MDS) is one of a group of cancers in which immature blood cells in the bone marrow do not mature, and as a result, do not develop into healthy blood cells. Early on, no symptoms typically are seen. Later, symptoms may ...

s "modest clinical activity was observed". 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, metastatic melanoma, and advanced solid tumors.

References

External links

Pevonedistat
structure and formula Cancer treatments Human proteins Orphan drugs

Target of pevonedistat

Mechanism of action

Clinical trials

References

Further reading

External links