PT2385

Antagonist of EPAS1

Structure

Information

  • EPAS1
  • Antagonist
  • up to 1 uM

In Vitro Validations

Uniprot ID: Q99814
Target Class: Transcription factor
Target SubClass: Hypoxia-Inducible Factor
Potency: Kd
Potency Value: < 50 nM
Potency Assay: ITC Binding Affinity
PDB ID for probe-target interaction (3D structure): 6E3S 5TBM
Structure-activity relationship: Yes
Target aliases:
Endothelial PAS domain-containing protein 1, PASD2 ...

DOI Reference: 10.1021/acs.jmedchem.8b01196

Uniprot ID: Q99814
Target Class: Transcription factor
Target SubClass: Hypoxia-Inducible Factor
Potency: IC50
Potency Value: 12 ± 5 nM
Potency Assay: Scintillation proximity assay with PAS-B* domain
PDB ID for probe-target interaction (3D structure): --
Target aliases:
Endothelial PAS domain-containing protein 1, PASD2 ...

DOI Reference: 10.1021/acs.jmedchem.8b01196

Uniprot ID: Q99814
Target Class: Transcription factor
Target SubClass: Hypoxia-Inducible Factor
Potency: Kd
Potency Value: 167 nM
Potency Assay: Measured by MST
PDB ID for probe-target interaction (3D structure): --
Target aliases:
Endothelial PAS domain-containing protein 1, PASD2 ...

DOI Reference: 10.1021/acs.jmedchem.8b01196

In Cell Validations

In Vivo Data

Off-Target Selectivity Assesments

Potency end-point : HIF-1alpha not detected
Potency assay (off target): ITC
Probe Selectivity in Cell:

0/40 kinase selectivity (<70% activity remaining at 10 μM)

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SERP ratings and comments


SERP Ratings

In Cell Rating
In Model Organisms

SERP Comments:

There are multiple lines of convincing evidence to support meaningful HIF2α modulation by PT-2385 in cell-free, cellular, and in vivo assays. This includes nanomolar cell-free target inhibition, x-ray crystal structures, ITC, convincing SAR, and activity consistent with HIF2α  engagement in multiple cellular and in vivo assays. I recommend including an inactive control analog in cellular assays, and in vivo assays if possible.

(last updated: 20 May 2021 )

SERP Ratings

In Cell Rating
In Model Organisms

(last updated: 4 Jun 2021 )

SERP Ratings

In Cell Rating
In Model Organisms

SERP Comments:

This is a promising HiF-2a antagonist with a high affinity to target, high cell potency, expected cellular effects (in vitro and in vivo), good in vivo PK and toxicology profiles, and very good selectivity properties.

(last updated: 4 Jun 2021 )