Delving into the Latest Updates on LMP2/7 inhibitor(Principia Biopharma) with Synapse

Overview

Basic Info

Drug Type

Small molecule drug

Synonyms-

Target

PSMB8 x PSMB9

Action

inhibitors

Mechanism

PSMB8 inhibitors(proteasome 20S subunit beta 8 inhibitors), PSMB9 inhibitors(proteasome 20S subunit beta 9 inhibitors)

Therapeutic Areas

Immune System Diseases

Active Indication-

Inactive Indication

Autoimmune Diseases

Originator Organization

Principia Biopharma, Inc.

Active Organization-

Inactive Organization

Kezar Life Sciences, Inc.Takeda Pharmaceuticals International, Inc.

Principia Biopharma, Inc.

License Organization-

Drug Highest PhasePendingPreclinical

First Approval Date-

Regulation-

Author: Yang Xuan ; Wei Xie ; Hongyan Wang ; Xinglong Ma ; Bianhong Zhang ; Liangfang Yao ; Jianru Xiao ; Xiaotao Li ; Tianyuan Meng ; Lei Li ; Tianzhen Wang ; Yanyan Xue ; Lei Zhou ; Abdus Saboor Shah ; Hao Wang ; Shiwang Shang ; Robb E. Moses ; Pei Zhang ; Yanyang Xia ; Xiaoshuang Wang ; Xueqing Ma ; Qing Fu

For quite a long time, the 11S proteasome activator REGɑ and REGβ, but not REGγ, are known to control immunoproteasome and promote antigen processing. Here, we demonstrate that REGγ functions as an inhibitor for immunoproteasome and autoimmune disease. Depletion of REGγ promotes MHC class I-restricted presentation to prime CD8⁺ T cells in vitro and in vivo. Mice deficient for REGγ have elevation of CD8⁺ T cells and DCs, and develop age-related spontaneous autoimmune symptoms. Mechanistically, REGγ specifically interacts with phosphorylated STAT3 and promotes its degradation in vitro and in cells. Inhibition of STAT3 dramatically attenuates levels of LMP2/LMP7 and antigen presentation in cells lacking REGγ. Importantly, treatment with STAT3 or LMP2/7 inhibitor prevented accumulation of immune complex in REGγ^-/- kidney. Moreover, REGγ^-/- mice also expedites Pristane-induced lupus. Bioinformatics and immunohistological analyses of clinical samples have correlated lower expression of REGγ with enhanced expression of phosphorylated STAT3, LMP2 and LMP7 in human Lupus Nephritis. Collectively, our results support the concept that REGγ is a new regulator of immunoproteasome to balance autoimmunity.

100 Deals associated with LMP2/7 inhibitor(Principia Biopharma)

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R&D Status

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Autoimmune Diseases	Preclinical	United States	Principia Biopharma, Inc.	02 Oct 2018
Autoimmune Diseases	Preclinical	United States	Takeda Pharmaceuticals International, Inc.	02 Oct 2018
Autoimmune Diseases	Preclinical	United States	Kezar Life Sciences, Inc.	02 Oct 2018