HRX215

HRX215 : Inhibitor of MAP2K4

Structure

SERP Rating

In Cells

(1 ratings)

In Model Organisms

(1 ratings)

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Probe HRX215 is in the process of SERP review.

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Information

MAP2K4

Inhibitor

up to 3 uM

Probe Availability:

ProbeChem

In Vitro Validations

Uniprot ID: P45985

Target Class: Kinase

Target SubClass: STE

Potency: IC50

Potency Value: 20 nM

Potency Assay: Radiometric kinase activity assay

PDB ID for probe-target interaction (3D structure): --

Target aliases:

Dual specificity mitogen-activated protein kinase ...

DOI Reference: 10.1016/j.cell.2024.02.023

In Cell Validations

In Vivo Data

Off-Target Selectivity Assesments

Potency assay (off target): >100-fold selectivity against JNK1, BRAF, and MKK7

Potency assay, off target (cells): MRNA sequencing and transcriptomic analyses

Probe Selectivity in Cell:

analysis was conducted with mRNA obtained from hepatectomized mouse livers with shRNA-mediated MKK4 knockdown vs. hepatectomized HRX215-treated mouse livers and revealed highly correlative gene expression profiles, underlining HRX215’s selectivity

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SERP ratings and comments

SERP Ratings

In Cell Rating

In Model Organisms

SERP Comments:

Structure-guided optimization of the MKK4 off-target activity of vemurafenib culminated in the identification of HR215 which is currently investigated in clinical trials for the treatment of liver failure. HR215 is a double digit nanomolar inhibitor of MKK4 with good selectivity against JNK1, B-Raf and MKK7. An additional investigation in a full kinase panel would further strengthen the confidence in HR215 as a valuable chemical probe for MKK4. On-target binding to MKK4 was confirmed in a biochemical assay and by NMR spectroscopy (for a close analogue). Dose-dependent modulation of MKK4 activation triggering SAPK signaling via TLR4 was demonstrated in peripheral mononuclear cells (PBMCs) after stimulation with LPS. A mouse PK (po, 30mg/kg) revealed a cmax of 54µM and a half-life of 3.4 hours enabling further efficacy studies. In vivo efficacy of HR215 could be demonstrated in several mouse models (e.g. hepatocyte proliferation after hepatectomy; protection of hepatocytes from cell death after CCl4 injection). In addition, modulation of MKK4 activation was shown in vivo.

(last updated: 13 Aug 2024 )