Delving into the Latest Updates on PKCtheta inhibitors (Aqilion) with Synapse

Overview

Basic Info

Drug Type

Small molecule drug

Synonyms-

Target

PKCθ

Mechanism

PKCθ inhibitors(Protein kinase C theta inhibitors)

Therapeutic Areas

Immune System DiseasesDigestive System DisordersSkin and Musculoskeletal Diseases

Active Indication

Colitis, UlcerativeRheumatoid Arthritis

Inactive Indication-

Originator Organization

Aqilion AB

Active Organization

Aqilion AB

Inactive Organization-

Drug Highest PhasePreclinical

First Approval Date-

Regulation-

Activation-induced cell death is mediated by the TCR-induced expression of the Fas ligand (FasL) on the surface of T cells, followed by binding to its receptor Fas. FasL expression is induced by stimulating T cells with a combination of phorbol ester and Ca2+ ionophore, implicating a role for protein kinase C (PKC) in this process. However, the precise mechanisms that regulate FasL expression, including the contribution of distinct T cell-expressed PKC isoforms, are poorly understood. Herein, we report that PKCtheta, a Ca2+-independent PKC isoform that we have previously isolated as a PKC enzyme selectively expressed in T cells, plays an important role in these processes. A constitutively active PKCtheta mutant preferentially induced FasL expression and activated the corresponding gene promoter; conversely, a dominant-negative PKCtheta mutant blocked FasL expression induced by anti-CD3 or PMA plus ionomycin stimulation. Furthermore, PKCtheta synergized with calcineurin to provide a potent stimulus for FasL promoter activation. Full activation of the promoter required its binding sites for the transcription factors NF-AT, AP-1, and NF-kappaB. The biological significance of these findings is implicated by the finding that rottlerin, a selective PKCtheta inhibitor, blocked FasL induction by anti-CD3 or PMA plus ionomycin stimulation and, consequently, protected human Jurkat T cells and the mouse T cell hybridoma A1.1 from activation-induced cell death.

100 Deals associated with PKCtheta inhibitors (Aqilion)

Login to view more data