Methods to induce targeted protein degradation through bifunctional molecules

A bifunctional, determinant technology, applied or administered to animals or humans in the field of decoy

Active Publication Date: 2017-10-17
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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  • Methods to induce targeted protein degradation through bifunctional molecules
  • Methods to induce targeted protein degradation through bifunctional molecules
  • Methods to induce targeted protein degradation through 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 equiv) was dissolved in formic acid (11 mL, 0.2M) at room temperature and stirred for 75 hours. The mixture was concentrated under reduced pressure to give 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- 4-yl)oxy)acetamide trifluoroacetate (Fischer et al. Nature 2014, 512, 49).

[1064] (2) Synthetic dBET1

[1065] Combine JQ-acid (11.3 mg, 0.0281 mmol, 1 equivalent) and N-(4-aminobutyl)-2-((2-(2,6-dioxopiperidin-3-yl)-1,3 -Dioxoisoindolin-4-yl)oxy)acetamide trifluoroacetate (14.5 mg, 0.0281 mmol, 1 equiv) was dissolved in DMF (0.28 mL, 0.1 M) at room temperature. Then DIPEA (14.7 μL, 0.0843...

Embodiment 2

[1066] Embodiment 2: Synthesis of dBET4

[1067]

[1068] N-(4-aminobutyl)-2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-4- To a 0.1 M solution of ((R)oxy)acetamide trifluoroacetate salt in DMF (0.438 mL, 0.0438 mmol, 1.2 eq) was added (R)-JQ-acid (derived from ( R)-JQ1 prepared) (14.63 mg, 0.0365 mmol, 1 equiv). DIPEA (19.1 μL, 0.1095 mmol, 3 eq) and HATU (15.3 mg, 0.0402 mmol, 1.1 eq) were added and the mixture was stirred for 24 h, then diluted with MeOH and concentrated under reduced pressure. The crude material was purified by preparative HPLC to give 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)δ174.43,172.40,171.29,169.92,168.24,167.82,166.71,156.31,153.14,138.38,138.24,137.54,134.88,133.86,133.44,132....

Embodiment 3

[1069] Embodiment 3: synthetic dBET3

[1070]

[1071] 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 equiv) was added to JQ-acid (15.86 mg, 0.0396 mmol, 1 equiv). DIPEA (20.7 μl, 0.1188 mmol, 3 equiv) and HATU (16.5 mg, 0.0435 mmol, 1.1 equiv) were then added and the mixture was stirred for 24 hours before purification by preparative HPLC to give 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)δ174.38,171.26,171.19,170.26,168.86,168.21,167.76,166.72,156.27,153.14,138.44,138.36,138.19,134.87,133.71,132.31,131.57,131.51,129.90,129.86,121.81,119.36,117.95,69.48, 54.83, 50.52, 40.09, 39.76, 38.30, 32.09, 23.63, 14.40, 11.61. LC...

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Abstract

The present application provides bifunctional compounds which act as protein degradation inducing moieties. The present application also relates to methods for the targeted degradation of endogenous proteins through the use of the bifunctional compounds that link a cereblon-binding moiety to a ligand that is capable of binding to the targeted protein which can be utilized in the treatment of proliferative disorders. The present application also provides methods for making compounds of the application and intermediates thereof.

Description

[0001] related application [0002] This application requests 62 / 096,318 filed December 23, 2014, 62 / 128,457 filed March 4, 2015, 62 / 149,170 filed April 17, 2015, May 2015 The benefit and priority of U.S. Provisional Application Nos. 62 / 159,048, filed on July 8, and 62 / 189,502, filed on July 7, 2015, the contents of each of which are incorporated by reference in their entirety. Background technique [0003] The ubiquitin-proteasome pathway (UPP) is a key pathway to regulate key regulatory proteins and degrade misfolded or abnormal proteins. UPP is extremely important for multiple cellular processes and, if defective or unbalanced, contributes to the pathogenesis of various diseases. Through the action of E3 ubiquitin ligase, the covalent linkage of ubiquitin and specific protein substrates is realized. These ligases comprise more than 500 different proteins and are classified into classes defined by their E3 functionally active structural elements. [0004] Cerebellin (cer...

Claims

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Application Information

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Patent Type & Authority Applications(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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