Anti-Alpha Tubulin monoclonal antibody, clone VW-03 [Dyomics® 547]

Background and Purpose Charcot-Marie-Tooth (CMT) disease is the most common hereditary peripheral neuropathy. CMT type 1A (CMT1A) accounts for approximately 50% of CMT patients and is linked to PMP22 gene duplication. Histone deacetylase-6 (HDAC6) has pleiotropic effects, such as regulating lipid homeostasis and cellular stress. Although HDAC6 has been regarded as a promising drug target for neurodegenerative diseases, its inhibition has not yet been tested in CMT1A. Here we have tested the therapeutic potential of CKD-504, a clinical stage HDAC6 inhibitor, in a mouse model of CMT1A Experimental Approach The potency and selectivity of CKD-504 was evaluated, using a HDAC enzyme panel assay and western blots. The therapeutic potential of CKD-504 was evaluated using behavioural testing and electrophysiological assessments in the C22 mouse model of CMT1A. PMP22 protein expression and aggregation were analysed in mesenchymal stem cell-derived Schwann cells from CMT1A patients and sciatic nerves from C22 mice. Key Results The HDAC6 inhibitor, CKD-504, modulated molecular chaperon proteins such as HSP90 and HSP70, which are involved in the folding/refolding of proteins such as PMP22. CKD-504 treatment restored myelination in both mesenchymal stem cell-derived Schwann cells from CMT1A patients and sciatic nerves of C22 mice and improved the axonal integrity of the sciatic nerve, leading to behavioural, electrophysiological, and histological improvements in C22 mice. Conclusion and Implications A novel HDAC6 inhibitor, CKD-504, has potent therapeutic efficacy for CMT1A.

Glochidiol has been shown to have potentially antiproliferative activityin vitro, however its anticancer mechanisms specifically against lung cancer remain unknown. This study aimed to investigate the anti-lung cancer effects of glochidiol in HCC-44 cellsin vitroandin vivo. In the present study, glochidiol was found to have potent antiproliferative activity against lung cancer cell lines NCI-H2087, HOP-62, NCI-H520, HCC-44, HARA, EPLC-272H, NCI-H3122, COR-L105 and Calu-6 with IC(50)values of 4.12 mu M, 2.01 mu M, 7.53 mu M, 1.62 mu M, 4.79 mu M, 7.69 mu M, 2.36 mu M, 6.07 mu M and 2.10 mu M, respectively.In vivo, glochidiol was found to effectively inhibit lung cancer HCC-44 xenograft tumor growth in nude mice. Docking analysis found that glochidiol forms hydrogen bonds with residues of tubulin. Glochidiol was also found to inhibit tubulin polymerizationin vitrowith an IC(50)value of 2.76 mu M. Immunofluorescence staining and EBI competition assay suggest that glochidiol may interact with tubulin by targeting the colchicine binding site. Thus, glochidiol might be a novel colchicine binding site inhibitor with the potential to treat lung cancer.