CPI-1612

Protein target name:

CREBBP, EP300

Mechanism of action:

inhibitor

Reviewer suggested Concentration for use in cells:

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

Probe Availability

MedChemExpress

Probe Information

Target and Probe Information

Target Details

Target class:

Epigenetics

Subclass:

Bromodomain

HUGO ID:

HGNC:3373 HGNC:2348

Entrez gene ID:

2033 1387

UNIPROT ID:

Q09472 Q92793

Target alias:

p300; KAT3B; MKHK2; RSTS2; CBP; RSTS; KAT3A; MKHK1; RSTS1

Probe Details

Chemical Probes Portal ID:

CPP1832

Probe alias:

Compound 17, CPI-0701612

PubChem CID:

146014965

SMILES string:

C(#N)C1=CC=C(C=C1)[C@@H](CN[C@@H](C(=O)NC1=NC=C(C=C1)C=1C=NN(C1)C)C1=CC=CC=C1)C

InChi Key:

SEDFZSHSBUXKAC-NIYFSFCBSA-N

Control compound:

Compound 16

Orthogonal probe:

A-485GNE-049SGC-CBP30

Physico-chemical properties

NMR:

1H NMR (600 MHz, DMSO-d6): 1.23 (d, J = 6.8 Hz, 3H), 2.64- 2.69 (m, 3H), 3.02 (q, J = 6.8 Hz, 1H), 3.86 (s, 3H), 4.47 (d, J = 7.6 Hz, 1H), 7.24-7.45 (m, 7H), 7.75 (d, J = 8.4 Hz, 2H); 7.90 (s, 1H), 7.92-8.03 (m, 2H), 8.18 (s, 1H), 8.56 (d, J = 1.6 Hz, 1H), 10.52 (s, -NH, 1H).

13C NMR (150 MHz, DMSO-d6): 19.26, 38.68, (one peak obscured by DMSO), 53.90, 65.77, 108.90, 113.23, 118.37, 119.03, 124.69, 127.27, 127.51, 127.75, 128.31, 128.34, 132.19, 134.32, 135.90, 139.34, 144.29, 149.34, 151.69, 171.40.

Validation in Cells and Model Organisms

In vitro validation

On target activity

Potency:

IC50

8.1 nM

Potency assay:

scintillation proximity assays (SPA)

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

6V8N

Structure-activity relationship:

yes

In cell validation

On target activity in cells

Potency in cells:

EC50

14 nM

Potency assay (cells):

H3K18Ac MSD assay (H3K18 = histone 3 lysine 18, MSD = meso scale discovery)

Off target activity in cells

Probe Selectivity in Cell:

Eurofins Safety44 off-target screening: 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).

In vivo validation

Organism:

Mice DogRat

Dose:

1.0 mg/Kg IV, 5.0 mg/Kg PO (M)0.5 mg/Kg IV, 1.0 mg/Kg PO (D)1.0 mg/Kg IV, 5.0 mg/Kg PO (R)

Route of delivery:

OralIntravenous

Plasma half life:

5.5 (D), 0.98 (M), 1.2 (R) h

Systemic clearance:

0.42 (D), 3.8 (M), 2.6 (R) L/h/kg

Organ of Interest

Organ (O):

Brain

Target engagement assay:

Compound 17 was administered orally to 18 male CD-1 mice. Plasma, brain, and CSF levels of compound 17 were then determined at multiple time points. See the Supporting Information for experimental details and additional data.

Primary Reference

Reference (doi):

10.1021/acsmedchemlett.0c00155

Endorsed probe

The Chemical Probes Portal endorses this compound as chemical probe for use in cells and in model organisms.

SAB Rating

Rating for use in Cells

3 review(s)

Rating for use in Model Organisms

3 review(s)

SAB Members

SAB 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.

Jul 14 2020 - 8:17pm

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.

Jul 30 2020 - 1:35pm

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.

Aug 28 2020 - 7:34am

CPI-1612

Probe Availability

Probe Information

Target Details

p300; KAT3B; MKHK2; RSTS2; CBP; RSTS; KAT3A; MKHK1; RSTS1

Probe Details

Physico-chemical properties

In vitro validation

In cell validation

In vivo validation

Primary Reference

Supporting Organizations

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CPI-1612

Probe Availability

Probe Information

Target Details

p300; KAT3B; MKHK2; RSTS2; CBP; RSTS; KAT3A; MKHK1; RSTS1

Probe Details

Physico-chemical properties

In vitro validation

In cell validation

In vivo validation

Primary Reference

Supporting Organizations

Interested in supporting the portal?