Delving into the Latest Updates on KI-696 with Synapse

Overview

Basic Info

Drug Type

Small molecule drug

Synonyms

Target

Mechanism

KEAP1 inhibitors(Kelch like ECH associated protein 1 inhibitors), Nrf2 inhibitors(Nuclear factor erythroid 2-related factor 2 inhibitors)

Therapeutic Areas

Respiratory DiseasesOther Diseases

Active Indication

acute stressPulmonary Disease, Chronic Obstructive

Inactive Indication-

Originator Organization

Astex Pharmaceuticals, Inc.

Active Organization

GSK Plc

Inactive Organization

Astex Pharmaceuticals, Inc.

Drug Highest PhasePreclinical

First Approval Date-

Regulation-

Structure/Sequence

Molecular FormulaC28H30N4O6S

InChIKeyZDNGJXBUEQNFBQ-GCJKJVERSA-N

CAS Registry1799974-70-1

Author: Eleuteri, Nicholas A ; Donovan, Katherine A ; Yue, Hong ; Du, Guangyan ; Nowak, Radosław P ; Jiang, Jie ; Gray, Nathanael S ; Fischer, Eric S ; Che, Jianwei ; Koide, Eriko ; Huang, Hubert T ; You, Inchul ; Yoon, Hojong ; He, Zhixiang ; Zhang, Tinghu ; Safaee, Nozhat ; Li, Zhengnian ; Nabet, Behnam ; Henning, Nathaniel J

Targeted protein degradation (TPD) uses small molecules to recruit E3 ubiquitin ligases into the proximity of proteins of interest, inducing ubiquitination-dependent degradation. A major bottleneck in the TPD field is the lack of accessible E3 ligase ligands for developing degraders. To expand the E3 ligase toolbox, we sought to convert the Kelch-like ECH-associated protein 1 (KEAP1) inhibitor KI696 into a recruitment handle for several targets. While we were able to generate KEAP1-recruiting degraders of BET family and murine focal adhesion kinase (FAK), we discovered that the target scope of KEAP1 was narrow, as targets easily degraded using a cereblon (CRBN)-recruiting degrader were refractory to KEAP1-mediated degradation. Linking the KEAP1-binding ligand to a CRBN-binding ligand resulted in a molecule that induced degradation of KEAP1 but not CRBN. In sum, we characterize tool compounds to explore KEAP1-mediated ubiquitination and delineate the challenges of exploiting new E3 ligases for generating bivalent degraders.

Food & Function

Cardamonin targets KEAP1/NRF2 signaling for protection against atherosclerosis

Article

Author: Meng, Huali ; Du, Lei ; Li, Hui ; Wang, Dongliang ; Zhang, Zhiyue ; Fan, Pengfei ; Wang, Yunyan ; Wu, Hao ; Guo, Xin ; Hao, Wenhao ; Zheng, Yan

Cardamonin and the Kelch domain inhibitor Ki696 structurally inhibit KEAP1, leading to the dissociation of NRF2 from KEAP1. This promotes NRF2 nuclear translocation and antioxidant gene expression, preventing atherosclerosis.

100 Deals associated with KI-696

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R&D Status

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
acute stress	Phase 1	US	Astex Pharmaceuticals, Inc.	-
Pulmonary Disease, Chronic Obstructive	Phase 1	US	Astex Pharmaceuticals, Inc.	-
acute stress	Preclinical	US	GSK Plc	-
Pulmonary Disease, Chronic Obstructive	Preclinical	US	GSK Plc	-