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Precision medicine in acute myeloid leukemia
Published in Debmalya Barh, 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).
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.
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).
An update on treatment of higher risk myelodysplastic syndromes
Published in Expert Review of Hematology, 2019
A growing number of targeted molecules are being tested in the treatment of higher risk MDS, for the most part in combination with HMAs. Results of ongoing advanced-phase clinical trials are highly expected: Hopefully, some first-line HMA-based therapies would improve CR rates and survival without increasing toxicities, thus defining new treatment standards beyond historical HMAs. In addition, personalized therapeutic strategies based on NGS-identified gene mutations and/or the understanding of MDS subtypes biology could be more possible than ever. For instance, we believe that TP53 modulators such as APR-246 are very promising in the treatment of MDS with complex karyotype and TP53 mutation: Those cases are associated with very poor prognosis, and it is thought that such treatments might change their natural history. In addition, protein neddylation inhibitors such as PEV and IDH inhibitors will occupy an important place in the therapeutic armamentarium of MDS. Finally, bi-specific T-cell engagers (BiTEs) and CAR-T cells are also believed to affect the management of MDS patients.