Delving into the Latest Updates on SR-4133 with Synapse

Overview

Basic Info

Drug Type

Small molecule drug

Synonyms

Target

CK1ε

Action

inhibitors

Mechanism

CK1ε inhibitors(casein kinase 1 epsilon inhibitors)

Therapeutic Areas

NeoplasmsUrogenital Diseases

Active Indication

Bladder Cancer

Inactive Indication-

Originator Organization

Queens College

Active Organization

Queens College

Inactive Organization-

Drug Highest PhasePreclinical

First Approval Date-

Regulation-

Structure/Sequence

Molecular FormulaC27H22F2N8O

InChIKeyDOPHVIBXJOSQHB-UHFFFAOYSA-N

CAS Registry2999645-23-5

Specific inhibition of a single kinase isoform is a challenging task due to the highly conserved nature of ATP-binding sites. Casein kinase 1 (CK1) δ and ε share 97% sequence identity in their catalytic domains. From a comparison of the X-ray crystal structures of CK1δ and CK1ε, we developed a potent and highly CK1ε-isoform-selective inhibitor (SR-4133). The X-ray co-crystal structure of the CK1δ-SR-4133 complex reveals that the electrostatic surface between the naphthyl unit of SR-4133 and CK1δ is mismatched, destabilizing the interaction of SR-4133 with CK1δ. Conversely, the hydrophobic surface area resulting from the Asp-Phe-Gly motif (DFG)-out conformation of CK1ε stabilizes the binding of SR-4133 in the ATP-binding pocket of CK1ε, leading to the selective inhibition of CK1ε. The potent CK1ε-selective agents display nanomolar growth inhibition of bladder cancer cells and inhibit the phosphorylation of 4E-BP1 in T24 cells, which is a direct downstream effector of CK1ε.

100 Deals associated with SR-4133

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