Full metadata record
DC Field | Value | Language |
---|---|---|
dc.contributor.author | Lim, Ye Seul | - |
dc.contributor.author | Yoo, Sun-Mi | - |
dc.contributor.author | Patil, Vineet | - |
dc.contributor.author | Kim, Han Wool | - |
dc.contributor.author | Kim, Hyun-Hwi | - |
dc.contributor.author | Suh, Beomseon | - |
dc.contributor.author | Park, Ji Youn | - |
dc.contributor.author | Jeong, Na-rae | - |
dc.contributor.author | Park, Chi Hoon | - |
dc.contributor.author | Ryu, Je Ho | - |
dc.contributor.author | Lee, Byung-Hoon | - |
dc.contributor.author | Kim, Pilho | - |
dc.contributor.author | Lee, Song Hee | - |
dc.date.accessioned | 2022-12-20T13:40:10Z | - |
dc.date.available | 2022-12-20T13:40:10Z | - |
dc.date.created | 2022-12-20 | - |
dc.date.issued | 2023-01 | - |
dc.identifier.issn | 2473-9529 | - |
dc.identifier.uri | http://hdl.handle.net/20.500.11750/17242 | - |
dc.description.abstract | Bruton tyrosine kinase (BTK) is an important signaling hub that activates the B-cell receptor (BCR) signaling cascade. BCR activation can contribute to the growth and survival of B-cell lymphoma or leukemia. The inhibition of the BCR signaling pathway is critical for blocking downstream events and treating B-cell lymphomas. Herein, we report potent and orally available proteolysis-targeting chimeras (PROTACs) that target BTK to inactivate BCR signaling. Of the PROTACs tested, UBX-382 showed superior degradation activity for wild-type (WT) and mutant BTK proteins in a single-digit nanomolar range of half-maximal degradation concentration in diffuse large B-cell lymphoma cell line. UBX-382 was effective on 7 out of 8 known BTK mutants in in vitro experiments and was highly effective in inhibiting tumor growth in murine xenograft models harboring WT or C481S mutant BTK–expressing TMD-8 cells over ibrutinib, ARQ-531, and MT-802. Remarkably, oral dosing of UBX-382 for <2 weeks led to complete tumor regression in 3 and 10 mg/kg groups in murine xenograft models. UBX-382 also provoked the cell type–dependent and selective degradation of cereblon neosubstrates in various hematological cancer cells. These results suggest that UBX-382 treatment is a promising therapeutic strategy for B-cell–related blood cancers with improved efficacy and diverse applicability. © 2022 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved. |
- |
dc.language | English | - |
dc.publisher | American Society of Hematology | - |
dc.title | Orally bioavailable BTK PROTAC active against wild-type and C481 mutant BTKs in human lymphoma CDX mouse models | - |
dc.type | Article | - |
dc.identifier.doi | 10.1182/bloodadvances.2022008121 | - |
dc.identifier.wosid | 000919671900001 | - |
dc.identifier.scopusid | 2-s2.0-85146458437 | - |
dc.identifier.bibliographicCitation | Blood Advances, v.7, no.1, pp.92 - 105 | - |
dc.description.isOpenAccess | TRUE | - |
dc.subject.keywordPlus | BRUTONS TYROSINE KINASE | - |
dc.subject.keywordPlus | TARGETED PROTEIN-DEGRADATION | - |
dc.subject.keywordPlus | NF-KAPPA-B | - |
dc.subject.keywordPlus | RECEPTOR | - |
dc.subject.keywordPlus | ACTIVATION | - |
dc.subject.keywordPlus | RESISTANCE | - |
dc.subject.keywordPlus | IBRUTINIB | - |
dc.subject.keywordPlus | DESIGN | - |
dc.subject.keywordPlus | INHIBITION | - |
dc.subject.keywordPlus | COMPLEX | - |
dc.citation.endPage | 105 | - |
dc.citation.number | 1 | - |
dc.citation.startPage | 92 | - |
dc.citation.title | Blood Advances | - |
dc.citation.volume | 7 | - |
dc.description.journalRegisteredClass | scie | - |
dc.description.journalRegisteredClass | scopus | - |
dc.relation.journalResearchArea | Hematology | - |
dc.relation.journalWebOfScienceCategory | Hematology | - |
dc.type.docType | Article | - |