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Orally bioavailable BTK PROTAC active against wild-type and C481 mutant BTKs in human lymphoma CDX mouse models

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 t...

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Autores principales: Lim, Ye Seul, Yoo, Sun-Mi, Patil, Vineet, Kim, Han Wool, Kim, Hyun-Hwi, Suh, Beomseon, Park, Ji Youn, Jeong, Na-rae, Park, Chi Hoon, Ryu, Je Ho, Lee, Byung-Hoon, Kim, Pilho, Lee, Song Hee
Formato: Online Artículo Texto
Lenguaje:English
Publicado: The American Society of Hematology 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9827040/
https://www.ncbi.nlm.nih.gov/pubmed/36269842
http://dx.doi.org/10.1182/bloodadvances.2022008121
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author Lim, Ye Seul
Yoo, Sun-Mi
Patil, Vineet
Kim, Han Wool
Kim, Hyun-Hwi
Suh, Beomseon
Park, Ji Youn
Jeong, Na-rae
Park, Chi Hoon
Ryu, Je Ho
Lee, Byung-Hoon
Kim, Pilho
Lee, Song Hee
author_facet Lim, Ye Seul
Yoo, Sun-Mi
Patil, Vineet
Kim, Han Wool
Kim, Hyun-Hwi
Suh, Beomseon
Park, Ji Youn
Jeong, Na-rae
Park, Chi Hoon
Ryu, Je Ho
Lee, Byung-Hoon
Kim, Pilho
Lee, Song Hee
author_sort Lim, Ye Seul
collection PubMed
description 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.
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spelling pubmed-98270402023-01-10 Orally bioavailable BTK PROTAC active against wild-type and C481 mutant BTKs in human lymphoma CDX mouse models Lim, Ye Seul Yoo, Sun-Mi Patil, Vineet Kim, Han Wool Kim, Hyun-Hwi Suh, Beomseon Park, Ji Youn Jeong, Na-rae Park, Chi Hoon Ryu, Je Ho Lee, Byung-Hoon Kim, Pilho Lee, Song Hee Blood Adv Regular Article 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. The American Society of Hematology 2022-10-26 /pmc/articles/PMC9827040/ /pubmed/36269842 http://dx.doi.org/10.1182/bloodadvances.2022008121 Text en © 2023 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. https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
spellingShingle Regular Article
Lim, Ye Seul
Yoo, Sun-Mi
Patil, Vineet
Kim, Han Wool
Kim, Hyun-Hwi
Suh, Beomseon
Park, Ji Youn
Jeong, Na-rae
Park, Chi Hoon
Ryu, Je Ho
Lee, Byung-Hoon
Kim, Pilho
Lee, Song Hee
Orally bioavailable BTK PROTAC active against wild-type and C481 mutant BTKs in human lymphoma CDX mouse models
title Orally bioavailable BTK PROTAC active against wild-type and C481 mutant BTKs in human lymphoma CDX mouse models
title_full Orally bioavailable BTK PROTAC active against wild-type and C481 mutant BTKs in human lymphoma CDX mouse models
title_fullStr Orally bioavailable BTK PROTAC active against wild-type and C481 mutant BTKs in human lymphoma CDX mouse models
title_full_unstemmed Orally bioavailable BTK PROTAC active against wild-type and C481 mutant BTKs in human lymphoma CDX mouse models
title_short Orally bioavailable BTK PROTAC active against wild-type and C481 mutant BTKs in human lymphoma CDX mouse models
title_sort orally bioavailable btk protac active against wild-type and c481 mutant btks in human lymphoma cdx mouse models
topic Regular Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9827040/
https://www.ncbi.nlm.nih.gov/pubmed/36269842
http://dx.doi.org/10.1182/bloodadvances.2022008121
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