{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,1,15]],"date-time":"2026-01-15T21:03:24Z","timestamp":1768511004815,"version":"3.49.0"},"posted":{"date-parts":[[2024,5,17]]},"group-title":"Cancer Biology","reference-count":0,"publisher":"openRxiv","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2024,5,17]]},"abstract":"<jats:p>Multiple myeloma is a plasma cell malignancy with poor prognosis despite the recent development of new therapeutic options. Histone deacetylase 6 (HDAC6) is overexpressed in multiple myeloma patients and may be involved in the acquisition of resistance to conventional anti-proteasome treatments. Beyond displaying a deacetylase catalytic activity, HDAC6 can recognize ubiquitinated motifs from misfolded proteins through its C-terminal ZnF-UBP binding domain and send the defective proteins to the aggresome for degradation. Here, we explore the role of the ZnF-UBP binding domain of HDAC6 in the function of multiple myeloma cells. A non-functional ZnF-UBP domain containing a 2-residue mutation in the binding site was designed and the absence of ubiquitin binding was confirmed in a cell-free assay. Molecular docking simulations and electrostatic calculations revealed a significant decrease in the electrostatic potential of the mutated peptide, which is crucial for the stability of the complex with ubiquitin. A multiple myeloma cell line containing the non-functional ZnF-UBP domain was then engineered. Although the deacetylase activity of HDAC6 was maintained in these cells, they showed reduced cell growth, impaired aggresome formation and a dysregulated gene expression profile that was more pronounced than cells entirely deficient in HDAC6. These results indicate that a non-functional ZnF-UBP binding domain impacts the function of multiple myeloma cells. Based on these findings, a series of quinazolinylpropanoic acid derivatives was synthesized to explore the inhibitory activity of small molecules to this domain. We propose that ZnF-UBP binding domain inhibitors should be further evaluated as potential therapeutic agents in multiple myeloma.<\/jats:p>","DOI":"10.1101\/2024.05.14.594071","type":"posted-content","created":{"date-parts":[[2024,5,17]],"date-time":"2024-05-17T20:45:21Z","timestamp":1715978721000},"source":"Crossref","is-referenced-by-count":0,"title":["Selective molecular inhibition of the HDAC6 ZnF-UBP binding domain impairs multiple myeloma cell proliferation"],"prefix":"10.64898","author":[{"given":"Rafael","family":"Rincon","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Isabel F","family":"Coira","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Antoine","family":"Richieu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Fedaa","family":"Attana","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Muriel","family":"Urwyler","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2650-2925","authenticated-orcid":false,"given":"Shozeb","family":"Haider","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3862-4583","authenticated-orcid":false,"given":"Carole","family":"Bourquin","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Philippe","family":"Bertrand","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1523-1907","authenticated-orcid":false,"given":"Muriel","family":"Cuendet","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"54368","container-title":[],"original-title":[],"link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.1101\/2024.05.14.594071","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,1,15]],"date-time":"2026-01-15T06:27:09Z","timestamp":1768458429000},"score":1,"resource":{"primary":{"URL":"http:\/\/biorxiv.org\/lookup\/doi\/10.1101\/2024.05.14.594071"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,5,17]]},"references-count":0,"URL":"https:\/\/doi.org\/10.1101\/2024.05.14.594071","relation":{},"subject":[],"published":{"date-parts":[[2024,5,17]]},"subtype":"preprint"}}