| Autor: |
Ye Seul Lim, Sun-Mi Yoo, Vineet Patil, Han Wool Kim, Hyun-Hwi Kim, Beomseon Suh, Ji Youn Park, Na-rae Jeong, Chi Hoon Park, Je Ho Ryu, Byung-Hoon Lee, Pilho Kim, Song Hee Lee |
| Rok vydání: |
2022 |
| Předmět: |
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| Zdroj: |
Blood advances. |
| ISSN: |
2473-9537 |
| Popis: |
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 |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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