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Inhibiting cyclic amp-responsive element-binding protein (CREB)

A compound and composition technology applied in the field of cyclic AMP-responsive element binding proteins

Pending Publication Date: 2021-12-31
FORMA THERAPEUTICS INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Chemical inhibition of CBP / p300 with intrinsic acetyltransferase enzymatic activity is more feasible than blocking transcription factors with small molecules, as the discovery of chemical inhibitors of transcription factors has proven to be extremely challenging

Method used

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  • Inhibiting cyclic amp-responsive element-binding protein (CREB)
  • Inhibiting cyclic amp-responsive element-binding protein (CREB)
  • Inhibiting cyclic amp-responsive element-binding protein (CREB)

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0143] Example 1 - Preparation of Compounds, Solid Forms and Salts

[0144] Example 1.a - Preparation of Amorphous Free Base + Form

[0145] (1R,3R)-3-[(7S)-2-[(R)-(5-fluoro-2-methoxyphenyl)(hydroxy)methyl]-6-(methoxycarbonyl)-7 -Methyl-3H,6H,7H,8H,9H-imidazo[4,5-f]quinolin-3-yl]cyclohexane-1-carboxylic acid (1);

[0146] (1R,3R)-3-[(7S)-2-[(S)-(5-fluoro-2-methoxyphenyl)(hydroxy)methyl]-6-(methoxycarbonyl)-7 -Methyl-3H,6H,7H,8H,9H-imidazo[4,5-f]quinolin-3-yl]cyclohexane-1-carboxylic acid (1')

[0147] Synthesis of intermediate 2-(5-fluoro-2-methoxyphenyl)-2-hydroxyacetic acid

[0148]

[0149] Step 1. 2-(5-Fluoro-2-methoxyphenyl)-2-[(trimethylsilyl)oxy]acetonitrile

[0150] ZnI 2 (1.6mg, 0.01mmol, a solution of 5-fluoro-2-methoxybenzaldehyde (1.54g, 9.99mmol) in trimethylsilanecarbonitrile (1.5mL, 11.25mmol) was stirred for 1 hour. The resulting mixture was Concentration under vacuum. The resulting crude product was purified by silica gel chromatography (eluting wit...

Embodiment 2

[0187] Example 2 - Kinetic Solubility Evaluation

[0188] The solubility of Form A HCl salt, Form B tosylate salt, and Form A free form was measured in water, SGF, FaSSIF and FeSSIF at 37°C with a solids loading of approximately 10 mg / mL (calculated as free base). All solubility samples were kept rotating at 25 rpm at 37°C and samples were taken at 1 h, 4 h and 24 h. The supernatant was extracted by centrifugation before filtration and used for solubility and pH measurements. The residual solid was collected for XRPD characterization. The results are summarized in Figure 7 middle.

Embodiment 3

[0189] Example 3 - HTRF Biochemical Assay of CBP and BRD4 Activity

[0190] The ability of amorphous Compound 1 to selectively inhibit CBP was determined using the following HTRF biochemical assays of CBP and BRD4 activity. Compound 2 was used as a reference compound:

[0191]

[0192] The assay was performed in an assay buffer containing 50 mM Hepes (pH 7.5, (0.5M Hepes, pH 7.5 solution; Teknova H1575)), 0.5 mM GSH, 0.01% BGG (0.22 μM filtered, Sigma, G7516-25G), 0.005% BSA (0.22 μM filtered, EMD Millipore Corporation, 126575) and 0.01% Triton X-100 (Sigma, T9284-10L). Nanoliter volumes of 10-point, 3-fold serial dilutions in DMSO were pre-distributed into 1536 assay plates (Corning, #3724BC) at final test concentrations ranging from 33 μM to 1.7 nM, highest to lowest dose, respectively. 3 μL 2x protein and 3 μL 2x peptide ligand were added to assay plates (pre-imprinted with compounds). Plates were incubated at room temperature for various times before measuring the ...

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Abstract

The present disclosure is directed to solid and salt forms of inhibitors of the CBP / p300 family of bromodomains made up of salts and crystalline forms of Formula (I). The compounds can be useful in the treatment of disease or disorders associated with the inhibition of the CBP / p300 family of bromodomains. For instance, the disclosure is concerned with compounds and compositions for inhibition of the CBP / p300 family of bromodomains, methods of treating diseases or disorders associated with the inhibition of CBP / p300 family of bromodomains (e.g., certain forms of cancer), and methods of synthesis of these compounds.

Description

[0001] Cross References to Related Applications [0002] This application claims the benefit of U.S. Provisional Patent Application No. 62 / 819,482, filed March 15, 2019, which is hereby incorporated by reference herein in its entirety. technical field [0003] The present disclosure relates to solid and salt forms of compounds and compounds that inhibit p300 (also known as EP300 and KAT3B) binding protein and / or cyclic AMP-response element binding protein (CREB) (CBP, also known as KAT3A) (p300 A cell paralog) approach. The compounds are useful in the treatment of certain forms of cancer. Background technique [0004] CBP / p300 is a lysine acetyltransferase that catalyzes the attachment of acetyl groups to lysine side chains of histones and other protein substrates. p300 (also known as EP300 and KAT3B) is a protein with multiple domains that bind a variety of proteins including many DNA-binding transcription factors. Cyclic AMP-response element binding protein (CREB) bindi...

Claims

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Application Information

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IPC IPC(8): A61K31/444A61K31/4545A61K31/4745
CPCA61K31/4745C07D471/04
Inventor G.卢克
Owner FORMA THERAPEUTICS INC
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