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

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

  • Blood Adv. 2023 Jan 10;7(1):92-105. doi: 10.1182/bloodadvances.2022008121.
Ye Seul Lim 1 Sun-Mi Yoo 1 Vineet Patil 2 3 Han Wool Kim 1 Hyun-Hwi Kim 1 Beomseon Suh 1 Ji Youn Park 1 Na-Rae Jeong 1 Chi Hoon Park 2 3 Je Ho Ryu 1 Byung-Hoon Lee 4 Pilho Kim 2 3 Song Hee Lee 1
Affiliations

Affiliations

  • 1 Ubix Therapeutics, Seoul, Republic of Korea.
  • 2 Therapeutics & Biotechnology Division, Korea Research Institute of Chemical Technology, Daejeon, Republic of Korea.
  • 3 Department of Medicinal Chemistry and Pharmacology, University of Science & Technology, Daejeon, Republic of Korea.
  • 4 Department of New Biology, Daegu Gyeongbuk Institute of Science and Technology, Daegu, Republic of Korea.
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.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-160142
    BTK降解剂
    Btk