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 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.

 

Comments：

BCR signaling is known to contribute to the growth and survival of B-cell lymphoma or leukemia, and inhibition of this pathway is critical for treating B-cell lymphomas.

The findings regarding UBX-382 are particularly interesting. UBX-382 showed superior degradation activity for both wild-type and mutant BTK proteins in a single-digit nanomolar range of half-maximal degradation concentration in diffuse large B-cell lymphoma cell lines. 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 both wild-type and C481S mutant BTK-expressing TMD-8 cells, outperforming other existing inhibitors such as ibrutinib, ARQ-531, and MT-802.

Moreover, the most remarkable aspect of UBX-382 is that oral dosing for less than 2 weeks led to complete tumor regression in 3 and 10 mg/kg groups in murine xenograft models. This suggests that UBX-382 has the potential to be a promising therapeutic strategy for B-cell-related blood cancers with improved efficacy and diverse applicability. Additionally, UBX-382 also provoked the cell type-dependent and selective degradation of cereblon neosubstrates in various hematological cancer cells.

Overall, the development of UBX-382 is a significant advancement in the treatment of B-cell-related blood cancers and provides a promising therapeutic option with improved efficacy and diverse applicability.

Related Products

Cat.No.	Product Name	Information
S6966	MT-802	MT-802 is a potent PROTAC that induces Bruton's tyrosine kinase (BTK) knockdown. MT-802 recruits BTK to the cereblon E3 ubiquitin ligase complex to trigger BTK ubiquitination and degradation via the proteasome. MT-802 has potential for treatment of C481S mutant chronic lymphocytic leukemia (CLL).

Related Targets

BTK