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Phytochemistry of Harmal
Published in Ephraim Shmaya Lansky, Shifra Lansky, Helena Maaria Paavilainen, Harmal, 2017
Ephraim Shmaya Lansky, Shifra Lansky, Helena Maaria Paavilainen
Desoxypeganine derivatives were developed as inhibitors of NEDD8-activating enzyme (NAE), which regulates specific degradation of proteins controlled by cullin-RING ubiquitin E3 ligases. The inhibition was believed, based on molecular modeling, to be related to blocking of ATP binding domains, and the derivatives were considered lead molecules for the development of more effective NAE inhibitors (Zhong H.J. et al. 2012, 2015).
Leukaemias
Published in Pat Price, Karol Sikora, Treatment of Cancer, 2014
The advances in understanding the cellular and molecular biology of MDS, are helping to identify future potential therapeutic targets. There are several agents currently in clinical trials in all risk categories of MDS. Candidate agents include MLN4924 (a novel NEDD8-activating enzyme [NAE] inhibitor), sotatercept (an activin-A chimeric receptor), rigosertib (a multikinase inhibitor) and agents such as Hedgehog inhibitors that target the malignant stem cell.211–215
Leukemias
Published in Pat Price, Karol Sikora, Treatment of Cancer, 2020
Erythropoiesis-maturing agents (EMAs), which are specific activin fusion proteins that act as ligand traps to neutralize negative regulators of erythropoiesis, have now been tested in patients with LR-MDS. Luspartercept (ACE-536) has shown ability to increase hemoglobin levels in LR-disease and is approved for patients with beta-thalassemia. The Phase II LR-MDS study reveals 63% erythroid responses with 38% achieving red-cell transfusion independence, particularly in patients with ringed sideroblasts or SF3B1-defined LR-MDS. The study met its primary end-points and is anticipated to be approved in 2020.131 Roxadustat (FG-4592) is an oral hypoxia-inducible factor inhibitor being tested in a Phase III study in LD-MDS in an effort to improve anemia.132 Imetelstat, a telomerase inhibitor, is in a Phase II/III study in red-cell transfusion-dependent and ESA-relapsed/refractory LR-MDS patients. Drugs aimed at improving thrombocytopenia, noted in about 50% of all LR-MDS patients, are also being tested. The TPO-receptor agonists romiplostim and elthrombopag have now been tested in Phase III studies and found to have platelet responses associated with survival benefits but are not approved as yet. Several other novel approaches are being tested, including second-generation HMAs, guadecitabine and ASTX727, and combinations of azacytidine with either lenalidomide, vorinostat (a TPO-receptor agonist), or pevonedistat (an NEDD8-activating enzyme).133 Several combination trials of venetoclax with azacytidine, including those adding tagraxofusp, a CD123-targeted drug, in the untreated and relapsed/refractory setting, and studies of immune checkpoint modulation with HMAs are also in progress. Other candidate approaches include vyxeos (CPX-351), a novel liposomal formulation of cytarabine and daunorubicin recently licensed for secondary AML or tMN, targeted IDH1/2 or FLT3 inhibitors, splicesome-modulator H3B-8800, CAR T-cells, and bispecific antibodies.
Discovery of dual tubulin-NEDDylation inhibitors with antiproliferative activity
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2023
NEDDylation as a biological process that affect the substrate’s activity, subcellular localisation, and conformation involves transfer of neural precursor cell-expressed developmentally downregulated 8 (NEDD8) in various cancers25. It is a three-step enzymatic cascade reaction by E1 NAE, NEDD8-conjugating enzymes E2 (Ubc12 or UBE2F), and NEDD8 E3 ligases26. To reveal the inhibitory effects of compound C11 on NEDDylation, a NEDDylation assay was performed according to our reported reference27. As shown in Figure 8, there are no Ubc12-NEDD8 and Ubc12-(NEDD8)2 bands without the treatment of ATP. Furthermore, expression levels of Ubc12-NEDD8 and Ubc12-(NEDD8)2 were decreased with the treatment of compound C11 in the presence of ATP. All these results obviously demonstrated that compound C11 inhibited NEDDylation in a ATP-dependent manner and compound C11 was a novel NEDDylation inhibitor.
An update on treatment of higher risk myelodysplastic syndromes
Published in Expert Review of Hematology, 2019
Pevonedistat (PEV) is an inhibitor of protein neddylation, a posttranslational protein modification that consists of conjugating the ubiquitin-like protein NEDD8 to its target proteins. The most characterized NEDD8 targets are cullin proteins, a family of hydrophobic scaffold proteins that provide support for E3 ubiquitin ligases: Neddylated cullins combines with RING proteins in a multi-subunit ubiquitin complex (cullin-RING ubiquitin ligases (CRLs)) which directs the degradation of specific substrates through the proteasome [74,75]. In the absence of NEDD8, CRL substrates (e.g. p27, CDT1, and Nrf-2) accumulate causing antiproliferative effects in tumor cells. In preclinical AML models, PEV in combination with AZA resulted in higher and synergistic antitumor activity compared with either agent alone [76]. A phase Ib study (NCT01814826) [75] reported that PEV + AZA combination was well tolerated and showed substantial clinical activity in patients aged >60 years with untreated AML ineligible for intensive chemotherapy. Among patients who received ≥6 cycles, response rates were as high as 83%, as well as in TP53-mutated patients (4/5, 80%), and median duration of response was 8 months. These results provided the rationale of an ongoing phase III study comparing the efficacy and safety of PEV + AZA to AZA as first-line treatment for higher risk MDS and low-blast AML (20–30% blasts) [77]: MDS patients are stratified by IPSS-R-risk groups and randomized 1:1 to receive PEV 20 mg/m2 intravenously on days 1, 3, and 5; plus AZA 75 mg/m2 on days 1–5, 8, and 9; or AZA alone, in 28-day cycles until progression or unacceptable toxicity.
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].