CPI-1612

Inhibitor of EP300, CREBBP

Structure

SERP Rating

In Cells

(3 ratings)

In Model Organisms

(3 ratings)

note: The Chemical Probes Portal only endorses compounds as chemical probes for use as specific and selective modulators of the proposed target if they receive three or more (3-4) stars.

Information

EP300
CREBBP

Inhibitor

50 nM
Reviewer recommended concentration: 50 nM for inhibition of H3K18ac (HCT-116), and proliferation of JEKO-1 (sensitive to CBP/EP300 inhibition)

DOI - 10.1021/acsmedchemlett.0c00155

Probe Availability:

In Vitro Validations

Uniprot ID: Q09472

Target Class: Epigenetic

Target SubClass: Histone acetyl transferase

Potency: IC50

Potency Value: 0.5 nM

Potency Assay: scintillation proximity assays (SPA) of full length EP300

PDB ID for probe-target interaction (3D structure): 6V8N

Structure-activity relationship: yes

Target aliases:

Histone acetyltransferase p300, P300, EP300, EP300 ...

DOI Reference: 10.1021/acsmedchemlett.0c00155

In Cell Validations

In Vivo Data

Off-Target Selectivity Assesments

Potency assay, off target (cells): Eurofins Safety44 off-target screening

Probe Selectivity in Cell:

Weak activity in a hERG binding assay (IC50 = 10.4 μM) and displayed moderate inhibition of CYP2C8 (IC50 = 1.9 μM) and CYP2C19 (IC50 = 2.7 μM), but it showed less inhibition of CYP3A4, CYP2D6, CYP1A2, CYP2B6, and CYP2C9 (>50 μM, 34 μM, >50 μM, 8.2 μM, 6.6 μM).

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SERP ratings and comments

SERP Ratings

In Cell Rating

In Model Organisms

SERP Comments:

HCT-116 cells are used to measure EC50 on the histone acetylation mark H3K18ac. JEKO-1 are used to measure inhibition of proliferation or GI50. The potency of CPI-1612 aligns in these two assays. In vivo: It is recommended for use in dogs and mice. In a mouse xenograft model of B-cell lymphoma dosed at 0.5 mg/kg PO b.i.d resulted in 67% inhibition of tumor growth and concomitant reduction of H3K27ac in plasma and H3K18ac in the tumor. CPI-1612 is not recommended for use in rats due to its poor bioavailability in this animal.

(last updated: 14 Jul 2020 )

SERP Ratings

In Cell Rating

In Model Organisms

SERP Comments:

CPI-1612 is a probe generated by Constellation Pharma following an extensive hit-to-lead medicinal chemistry campaign designed to optimize the scaffold to obtain an orally active compound against the HAT domain of CBP/p300 in animal models. CPI-1612 shows nM potency in in vitro assays and selectivity over other tested HAT domains, has favorable pharmcokinetic attributes in mice but not rats, and can be dosed orally. Notably, this probe engages p300 in a slightly distinct manner than another validated CBP/p300 HAT domain probe generated by Abbvie Pharma (A-485), establishing H-bond contacts with different residues and structured waters in the HAT domain. Thus, use of A-485 and CPI-1612 as orthogonal probes is recommeded.

(last updated: 30 Jul 2020 )

SERP Ratings

In Cell Rating

In Model Organisms

SERP Comments:

A potent and selective probe that is a good addition to chemical matter for this target. The increase in cellular potency and selectivity make this a welcome addition.

(last updated: 28 Aug 2020 )