Precision medicine in acute myeloid leukemia
Debmalya Barh in Precision Medicine in Cancers and Non-Communicable Diseases, 2018
CD33 antibody-drug conjugates such as gemtuzumab ozogamicin and vadastuximab talirine (SGN-CD33A) (Burnett et al., 2012; Daver et al., 2016; Minagawa et al., 2016; Table 10.9); Hedgehog inhibitors like sonidebig (erismodegib, LDE255), glasdegib (PF-04449913), and vismodegib; neddylation and subsequent ubiquitination inhibitors (pevonedistat); and Wnt signaling pathway inhibitors (Fukushima et al., 2016; Hanna and Shevde, 2016; Ma et al., 2015; Medler et al., 2015; Swords et al., 2017) together with standard chemotherapy are in ongoing trials. Further therapeutic approaches including NF-κB signaling pathway inhibition (Bosman et al., 2016; Fuchs 2010; Siveen et al., 2017; Zhou et al., 2015), PI3 K/AKT/mTOR signaling pathway inhibition, (Brenner et al., 2016; Fuchs 2011; Hauge et al., 2016) and targeting the S100A8/S100A9-TLR4-ERK/JNK/p38 pathway (Laouedj et al., 2017; Tamburini, 2017) were studied. Cell division cycle 25 (CDC25) protein phosphatases inhibition had antiproliferative effects on primary human AML cells for a subset of patients identified by gene expression profiling (Brenner et al., 2017).
Enhancing venetoclax activity in hematological malignancies
Published in Expert Opinion on Investigational Drugs, 2020
Pevonedistat (MLN4924) represents a potentially promising new agent in AML treatment. It is a first-in-class inhibitor of protein ‘neddylation,’ a post-translational protein modification that operates in parallel with ubiquitination to allow proteins to be targeted for proteasomal destruction. Pevonedistat blocks degradation of IκBα, resulting in inhibition of NF-kB, upon which LSCs are dependent for survival [99]. Pevonedistat also induces accumulation of the DNA licensing factor CDT1, leading to re-replication and DNA damage [100]. Pevonedistat has shown modest single-agent activity in AML [101] and MM [102], and when combined with azacitidine, the overall response rate was 50% in the former [103]. In preclinical studies involving AML cell lines and patient samples, pevonedistat induced accumulation of c-MYC, a substrate of NF-kB, that transactivates NOXA. NOXA specifically binds to and neutralizes MCL1, leading to less BAK binding to MCL1, resulting in apoptosis. Combination of venetoclax and pevonedistat in vitro interacted synergistically to induce apoptosis both in cell lines and patient samples [104]. Based in part upon these findings, there are currently two ongoing early phase clinical trials combining venetoclax, azacitidine, and pevonedistat (NCT04172844, NCT03862157).
Discovery of dual tubulin-NEDDylation inhibitors with antiproliferative activity
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2023
NEDDylation is catalysed by three-enzyme cascade including the E1 NEDD8-activating enzyme (NAE), E2 NEDD8-conjugating enzyme and E3 NEDD8 ligase, which could lead to attachment of ubiquitin-like NEDD8 to a substrate protein on a lysine residue8. Many studies have illustrated the close relationship between NEDDylation in multiple pathophysiological processes and different NEDDylation modulators were designed9. Compound 5 (Figure 2) as an orally bioavailable analogue inhibited both DCN1-mediated cullin neddylation and the DCN1-UBE2M protein-protein interaction10. Our group reported a novel tertiary amide derivative 6 as the NEDDylation activator to inhibit tumour progression in vitro and in vivo11. Compound 7 targeting NEDDylation displayed the potent activity MGC-803, EC-109, and PC-3 cells with IC50 values of 2.35, 10.1, and 5.71 μM12. All these findings showed that NEDDylation modulators might be potential anticancer agents.
Mantle cell lymphoma: insights into therapeutic targets at the preclinical level
Published in Expert Opinion on Therapeutic Targets, 2020
Neddylation is a posttranslational modification that involves the addition of the ubiquitin-like protein NEDD8 to a target protein. Neddylation is mediated by the NEDD8-activting enzyme (NAE). Pevonedistat is an investigational NAE inhibitor that alters proteasomal degradation of intracellular proteins. Pevonedistat has demonstrated promising preclinical activity in MCL [99].
Related Knowledge Centers
- Ubiquitin-Like Protein
- Nedd8
- Ubiquitin
- Isopeptide Bond
- Cullin
- Alzheimer's Disease
- Apoptosis
- Cell Cycle