China
Africa
Explore chapters and articles related to this topic
The Promise of Therapy with Embryonic Stem Cells
Published in Howard Green, Therapy with Cultured Cells, 2019
We investigated the possibility of improving the multiplication of the hES cell-derived keratinocytes by the introduction of exogenous genes known to promote multiplication, such as CDK4, E2F, BMI-1 and CBX7. Some of these had no effect but others had some effects, even if they were too small to be useful. In principle, these effects demonstrated that the introduction of exogenous genes could result in increased proliferative potential. Studies in the laboratory of James Rheinwald showed that a variety of other genes were able to increase life-span (Dabelsteen et al., 2009). The future of practical applications of hES cell-derived somatic cells depends on the increase of their proliferative potential by the introduction of exogenous genes.
Hypoxia-inducible factor (HIF) inhibitors: a patent survey (2016–2020)
Published in Expert Opinion on Therapeutic Patents, 2021
Hyun Seung Ban, Yoshikazu Uto, Hiroyuki Nakamura
China Medical University Taiwan disclosed the preparation of amino acid genipin esters and a pharmaceutical composition useful for the treatment of a cerebrovascular accident (CVA), which results in a rapidly progressing brain function loss caused by an abnormal blood supply to the brain [55]. CVA can be classified mainly into two main categories: ischemic stroke caused by blood clots that block or plug a blood vessel in the brain, and hemorrhagic stroke caused by breakage of blood vessels and bleeding into the brain. The invention is related to the preparation of a bicyclic compound 16 (Figure 3), and its pharmaceutical composition for treating CVA. The nerve cell protective effect of compound 16 was confirmed by an in vitro cell assay, and a treatment effect of compound 16 on CVA was verified by an ischemic stroke animal model. Compound 16 showed a therapeutic effect on the stroke through the HIF-1α-Bmi-1 signaling pathway [56] and stimulated the proliferation and self-renewal ability of neural stem cells. Activated HIF-1α was found to directly bind to the polycomb repressor complex 1-chromobox7 (CBX7) to activate CBX7 expression under hypoxia. During CBX7 upregulation, the same levels of PRC1 of Bmi-1 was observed in the ischemic brains [57].
Beyond EZH2: is the polycomb protein CBX2 an emerging target for anti-cancer therapy?
Published in Expert Opinion on Therapeutic Targets, 2019
Maïka Jangal, Benjamin Lebeau, Michael Witcher
CBX7 is highly associated with multiple diseases phenotypes, and as such, it is the most widely studied CBX family member and the development of small molecules targeting CBX paralogues have focused on CBX7 to prevent its interaction with H3K27me3. To date, most of these inhibitors seem to hold poor specificity, targeting multiple members of the CBX family.
Novel chromobox 2 inhibitory peptide decreases tumor progression
Published in Expert Opinion on Therapeutic Targets, 2023
Lindsay W. Brubaker, Donald S. Backos, Vu T. Nguyen, Philip Reigan, Tomomi M Yamamoto, Elizabeth R. Woodruff, Ritsuko Iwanaga, Michael F. Wempe, Vijay Kumar, Christianne Persenaire, Zachary L. Watson, Benjamin G. Bitler
All the CBX proteins contain CD, that binds to methylated histones leading to further chromatin modification via RING1A/BMI1 mediated ubiquitin ligase and differential regulate gene expression. However, compared to all the CBX proteins associated with PRC1, CBX2 has a unique and intact A/T-hook domain [34] (Figure S3). The A/T-hook domain allows for CBX2 to directly interact with DNA. The current crystal structures of CBX proteins do not contain an intact A/T-hook domain; therefore, we used computational-based modeling to generate homology models of CBX2 and CBX4. These models comprised the CD and A/T-hook domains (for CBX4 – amino acids that span the similar region compared to CBX2 [Figure S3]) and revealed that compared to CBX4 the A/T-hook domain of CBX2 has a unique open pocket conformation and charged surface, that could be exploitable for the development of CBX2-selective inhibitors (Figure 2a-d). Computational models of the crystal structures of CBX2 and CBX4 were modeled with the oligopeptide UNC3866. UNC3866 was developed to target the CD and demonstrated specificity for CBX7 with a significantly reduced specificity for other CBX proteins including CBX2 (12-fold less specific) [23]. In this study, we modified UNC3866 by extending the peptide toward the A/T-hook domain by adding complementary amino acid residues to optimize interactions with those of the binding cleft of CBX2. Using a 20-ns trajectory to assess the stability of peptide interactions with the modeled CBX2, six peptides were identified and ultimately four of the six peptides were identified as optimal for in vitro testing. These peptides were docked into the binding cleft of CBX2 via metadynamics, minimized, and subjected to a molecular dynamics simulation to identify peptides that would bind in the correct orientation for CBX2 inhibition. In addition, to enhance peptide stability and cell penetration the N-terminus of the peptides was acetylated and the C-terminus was aminated, and to mimic the CD recognizing methylated histone a diethyl lysine residue was included and is not subject to endogenous de-methylase enzymes. These peptides were then synthesized for evaluation in ovarian cancer models.