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

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.

• Authors: 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
• Journal: Blood advances (Blood Adv) Vol. 7 Issue 1 Pg. 92-105 (01 10 2023) ISSN: 2473-9537 [Electronic] United States
• PMID: 36269842 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 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.

Chemical References

• Agammaglobulinaemia Tyrosine Kinase
• ARQ531
• Pyrimidines

Topics

• Humans
• Animals
• Mice
• Agammaglobulinaemia Tyrosine Kinase
• Pyrimidines (pharmacology, therapeutic use)
• Signal Transduction
• Disease Models, Animal
• Lymphoma, Large B-Cell, Diffuse (drug therapy, genetics)