Author: Chen, Ting ; Liu, Yao ; Chen, Jianjun ; Bao, Jingna ; Cai, Shumin ; Peng, Xiaopeng ; Huang, Junli ; He, Zengzhu ; Ma, Zeli ; Zeng, Zhenhua ; Yang, Zichao

As a critical upstream regulator of nuclear factor-κB (NF-κB) activation, Bruton's tyrosine kinase (BTK) has been identified to be an effective therapeutic target for the treatment of acute or chronic inflammatory diseases. Herein, we describe the design, synthesis and structure-activity-relationship analysis of a novel series of Ibrutinib-based BTK PROTACs by recruiting Cereblon (CRBN) ligase. Among them, compound 15 was identified as the most potent degrader with a DC₅₀ of 3.18 nM, significantly better than the positive control MT802 (DC₅₀ of 63.31 nM). Compound 15 could also degrade BTK protein in Lipopolysaccharide (LPS)-stimulated RAW264.7 cells, and suppress the mRNA expression and secretion of proinflammatory cytokines such as IL-1β and IL-6 by inhibiting NF-κB activation. Furthermore, compound 15 reduced inflammatory responses in a mouse zymosan-induced peritonitis (ZIP) model. Our findings demonstrated for the first time that targeting BTK degradation by PROTACs might be an alternative option for the treatment of inflammatory disorders, and compound 15 represents one of the most efficient BTK PROTACs (DC₅₀ = 3.18 nM; D_max = 99.90%; near 100% degradation at 8 h) reported so far and could serve as a lead compound for further investigation as an anti-inflammatory agent.

10 Jan 2023·Blood Advances

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

Article

Author: Kim, Han Wool ; Jeong, Na-rae ; Kim, Pilho ; Ryu, Je Ho ; Yoo, Sun-Mi ; Lee, Byung-Hoon ; Suh, Beomseon ; Lee, Song Hee ; Park, Ji Youn ; Patil, Vineet ; Park, Chi Hoon ; Lim, Ye Seul ; Kim, Hyun-Hwi

AbstractBruton 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.

01 Feb 2022·Clinical and Translational OncologyQ3 · MEDICINE

MicroRNA-802 promotes the progression of osteosarcoma through targeting p27 and activating PI3K/AKT pathway

Q3 · MEDICINE

Article

Author: Zhang, Q M ; Li, C J ; Jia, S ; Xia, Y F ; Li, Y H ; Gao, L F

PURPOSEIncreasing evidences suggest dysfunctions of microRNAs (miRNAs) are playing important part in tumors. Therefore, the role of miR-802 in osteosarcoma (OS) was exploited. The object was to evaluate the effect of miR-802 and verify its influence on p27 Kip1 (p27) in OS.METHODSRT-qPCR experiment was used to detect miR-802 and p27 expression in OS tissues and cells. We explored the function of miR-802 through Transwell assays. The phosphoinositide 3-kinase (PI3K)/AKT serine/threonine kinase pathway and epithelial-mesenchymal transition (EMT) was detected by Western blot assays. Luciferase assay was used to testify the target of miR-802.RESULTSMiR-802 expression was elevated in OS, which was related to poor clinical outcome in OS patients. MiR-802 overexpression promoted OS migration, invasion and EMT. Further, p27 is a direct target of miR-802. P27 elevation counteracted the promotion effect of OS on EMT, migration and invasion induced by miR-802. In addition, miR-802 overexpression inactivated PI3K/AKT pathway via targeting p27 in OS.CONCLUSIONMiR-802 promoted the progress of EMT, migration and invasion in OS via targeting p27. This newly identified miR-802/p27/PI3K/AKT axis may represent potential targets for OS.

100 Deals associated with MT-802

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Indication	Highest Phase	Country/Location	Organization	Date
Chronic phase chronic myeloid leukemia	Preclinical	US	Yale University	-

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