Method for inducing target protein degradation by bifunctional molecules

A technology for targeting ligands and compounds, which is applied in or administered to animals or humans to induce induction

Active Publication Date: 2020-06-30
DANA FARBER CANCER INST INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

New approaches regarding possible targets and more general properties of different cell lines or different in vivo systems compared to existing approaches could potentially lead to the development of future drug treatments

Method used

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  • Method for inducing target protein degradation by bifunctional molecules
  • Method for inducing target protein degradation by bifunctional molecules
  • Method for inducing target protein degradation by bifunctional molecules

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[1059] Example 1: Synthesis of dBET1

[1060]

[1061] (1) Synthesis of JQ-acid

[1062] JQ1 (1.0 g, 2.19 mmol, 1 equivalent) was dissolved in formic acid (11 mL, 0.2 M) at room temperature and stirred for 75 hours. The mixture was concentrated under reduced pressure to obtain a yellow solid (0.99 g, quantitative yield), which was used without purification. 1 H NMR (400MHz, methanol-d 4 )δ7.50–7.36(m,4H),4.59(t,J=7.1Hz,1H),3.51(d,J=7.1Hz,2H), 2.70(s,3H), 2.45(s,3H), 1.71 (s, 3H). LCMS 401.33 (M+H).

[1063] Synthesis of N-(4-aminobutyl)-2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline- according to the previously published method 4-yl)oxy)acetamide trifluoroacetate (Fischer et al. Nature 2014, 512, 49).

[1064] (2) Synthesis of dBET1

[1065] Combine JQ-acid (11.3mg, 0.0281mmol, 1 equivalent) and N-(4-aminobutyl)-2-((2-(2,6-dioxopiperidin-3-yl)-1,3 -Dioxoisoindolin-4-yl)oxy)acetamide trifluoroacetate (14.5mg, 0.0281mmol, 1 equivalent) was dissolved in DMF (0.28mL, 0.1M) at room...

Embodiment 2

[1066] Example 2: Synthesis of dBET4

[1067]

[1068] Add N-(4-aminobutyl)-2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-4- (R)-JQ-acid (in a method similar to JQ-acid) was added to a 0.1M solution of acetamide trifluoroacetate in DMF (0.438mL, 0.0438mmol, 1.2 equivalents) R)-JQ1 preparation) (14.63mg, 0.0365mmol, 1 equivalent). DIPEA (19.1 microliters, 0.1095 mmol, 3 equivalents) and HATU (15.3 mg, 0.0402 mmol, 1.1 equivalents) were added, the mixture was stirred for 24 hours, then diluted with MeOH and concentrated under reduced pressure. The crude material was purified by preparative HPLC to obtain a yellow solid (20.64 mg, 0.0263 mmol, 72%). 1 H NMR (400MHz, methanol-d 4 )δ7.79(dd,J=8.4,7.4Hz,1H),7.51(d,J=7.3Hz,1H),7.47–7.39(m,5H),5.11–5.06(m,1H),4.75(s ,2H), 4.68(dd,J=8.8,5.5Hz,1H), 3.47–3.31(m,5H), 2.83–2.65(m,7H), 2.44(s,3H), 2.13–2.06(m,1H ), 1.68(s, 3H), 1.67-1.60(m, 4H). 13 C NMR(100MHz,cd 3 od)δ174.43,172.40,171.29,169.92,168.24,167.82,166.71,156.31,153.14,1...

Embodiment 3

[1069] Example 3: Synthesis of dBET3

[1070]

[1071] Add N-(2-aminoethyl)-2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-4- A 0.1 M solution of oxy)acetamide trifluoroacetate in DMF (0.475 mL, 0.0475 mmol, 1.2 equivalents) was added to JQ-acid (15.86 mg, 0.0396 mmol, 1 equivalent). Then DIPEA (20.7 microliters, 0.1188 mmol, 3 equivalents) and HATU (16.5 mg, 0.0435 mmol, 1.1 equivalents) were added, the mixture was stirred for 24 hours, and then purified by preparative HPLC to obtain a yellow solid (22.14 mg, 0.0292 mmol, 74%). 1 H NMR (400MHz, methanol-d 4 )δ7.82–7.75(m,1H),7.52–7.32(m,6H),5.04(dd,J=11.6,5.5Hz,1H), 4.76(d,J=3.2Hz,2H), 4.66(d ,J=6.6Hz,1H),3.58–3.35(m,6H), 2.78–2.58(m,6H), 2.48–2.41(m,3H), 2.11–2.02(m,1H), 1.70(d,J = 11.8Hz, 3H). 13 C NMR(100MHz,cd 3 od)δ174.38,171.26,171.19,170.26,168.86,168.21,167.76,166.72,156.27,153.14,138.44,138.36,138.19,134.87,133.71,132.31,131.57,131.51,129.90,129.86,121.81,119.36,117.95, 54.83, 50.52, 40.09, 39.76, 38.30, 32.09,...

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Abstract

The application provides bifunctional compounds that act as protein degradation inducing moieties. The present application also relates to methods of targeted degradation of endogenous proteins through the use of bifunctional compounds linking cerebellar protein binding moieties to ligands capable of binding to target proteins, which are useful in the treatment of proliferative disorders. The present application also provides methods for preparing the compounds of the present application and intermediates thereof.

Description

[0001] Related application [0002] This application requires No. 62 / 096,318 filed on December 23, 2014, No. 62 / 128,457 filed on March 4, 2015, No. 62 / 149,170 filed on April 17, 2015, May 2015 The rights and priority of U.S. Provisional Application No. 62 / 159,048 filed on 8th and U.S. Provisional Application No. 62 / 189,502 filed on July 7, 2015, the content of each of which is incorporated by reference in its entirety. Background technique [0003] The ubiquitin-proteasome pathway (UPP) is a key pathway that regulates key regulatory proteins and degrades misfolded or abnormal proteins. UPP is extremely important for multiple cell processes. If it is defective or unbalanced, it will cause various diseases. Through the action of E3 ubiquitin ligase, the covalent connection of ubiquitin and specific protein substrate is realized. These ligases contain more than 500 different proteins and are divided into multiple categories defined by their E3 functionally active structural elements...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D495/04C07D495/14C07D471/04C07D471/14C07D401/04A61K31/551A61P35/00
CPCC07D401/04C07D471/04C07D471/14C07D495/04C07D495/14C07D401/14C07D475/00C07D487/04A61P1/04A61P1/16A61P1/18A61P11/00A61P13/08A61P13/10A61P13/12A61P15/00A61P17/00A61P25/00A61P35/00A61P35/02C07J43/003
Inventor J·布拉德纳D·巴克利G·温特
Owner DANA FARBER CANCER INST INC
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