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Bifunctional compound capable of inducing PRC2 protein complex core subunit degradation, pharmaceutical composition and application

A compound, bifunctional technology, applied in the field of chemical medicine, can solve the problems of affecting the catalytic activity of HDAC, unable to effectively inhibit EZH2, unable to degrade various core subunits, etc., and achieve good anticancer activity, low toxicity, and good antitumor activity. Effect

Active Publication Date: 2021-06-08
WEST CHINA HOSPITAL SICHUAN UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

EED can also directly interact with the histone deacetyltransferase HDAC independent of PRC2 function, affecting the catalytic activity of HDAC
[0007] Therefore, the current EZH2 inhibitors or EED inhibitors are only used to inhibit the activity of PRC2, but they cannot effectively inhibit the oncogenic activities of EZH2, EED, etc. degraded to completely block the oncogenic activity of PRC2 complex subunits

Method used

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  • Bifunctional compound capable of inducing PRC2 protein complex core subunit degradation, pharmaceutical composition and application
  • Bifunctional compound capable of inducing PRC2 protein complex core subunit degradation, pharmaceutical composition and application
  • Bifunctional compound capable of inducing PRC2 protein complex core subunit degradation, pharmaceutical composition and application

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0064] This example provides the synthesis and related chemical data of nine bifunctional compounds G4-G12. The synthetic route of G4-G12 is as follows:

[0065]

[0066] The specific preparation process is:

[0067] The first step: preparation 1b, ammonolysis reaction.

[0068] 1a (3.28g, 20mmol, 1.0eq), 3-aminopiperidine-2,6-dione (3.1g, 24mmol, 1.2eq) was dissolved in 50mL of acetic anhydride, heated to reflux at 140°C for 6h, and decompressed after the reaction was completed The reaction solvent was removed by distillation, and the residue was poured into water, and a light gray precipitate was precipitated, filtered with suction, the filter cake was washed with water, and dried to obtain product 1b (3.84g, 71%). HRMS m / z calculated for C13H10N2O5[M+H]+: 275.0662, found: 275.0686.

[0069] The second step: 1c-1k general synthesis steps.

[0070] 1b (1mmol, 1.0eq), DIPEA (3mmol, 3.0eq) and dibromoalkane (1.2mmol, 1.2eq) were dissolved in DMF (10mL), and reacted at 85-1...

Embodiment 2

[0110] This example provides the synthesis and related chemical data of nine bifunctional compounds E4-E12. The synthetic route of E4-E12 is as follows:

[0111]

[0112] The specific preparation process is:

[0113] The first step: 2-methyl-3-bromo-5-nitrobenzoic acid methyl ester 2a (5.5g, 20mmol, 1.0eq), ammonium chloride (5.6g, 100mmol, 5.0eq) was dissolved in aqueous ethanol ( 60mL, H 2 O:EtOH=1:3), after heating up to 80°C, iron powder (11.2g, 200mmol, 10.0eq) was added three times. Thin-layer chromatography (TLC) detection reaction is completed after reacting 1h, and diatomaceous earth filter aids, and filtrate decompression distills off solvent, and residue is extracted through DCM, and Na 2 SO 4 Concentration after drying afforded product 2b (4.41 g, 92%) without further purification. 1 H NMR (400MHz, CDCl 3 )δ7.31(d,J=2.6Hz,1H),6.92(d,J=2.6Hz,1H),3.87(s,3H),3.82(s,2H),2.26(s,3H).HRMS m / z calculated for C 9 h 10 BrNO 2 [M+H] + :243.9967,found:243.9958. ...

Embodiment 3

[0149] This example provides the synthesis and related chemical data of nine bifunctional compounds S4-S12. The synthetic route of S4-S12 is as follows:

[0150]

[0151] The specific preparation process is:

[0152] The first step: S1 (4mmol) and S2 (4.4mmol) were dissolved in DMSO (10mL), HOAT (0.55g, 1.5mmol) and EDCI (0.84g, 2.2mmol) were added, and the reaction solution was stirred at 45°C for 20h. After the completion of the reaction monitored by TLC, the reaction solution was poured into ice water (100mL), stirred for 30min, precipitated out, filtered, washed with water, dried, dissolved in a mixture of methanol and chloroform (10:1), mixed, passed through a silica gel column layer Analysis and purification afforded yellow solid S3 (1.57 g). 1 H NMR (400MHz, Chloroform-d) δ12.78(s, 1H), 7.41(t, J=5.7Hz, 1H), 7.22(d, J=2.0Hz, 1H), 7.18(d, 2.0Hz, 1H ), 4.54(d, J=5.7Hz, 2H), 3.94(dt, J=11.6, 3.3Hz, 2H), 3.36–3.25(m, 2H), 3.02(q, J=7.0Hz, 2H), 2.95 (m,1H),2.93(dd,J=7...

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Abstract

The invention discloses a bifunctional compound capable of inducing PRC2 protein complex core subunit degradation, a pharmaceutical composition and application. The bifunctional compound comprises a compound as shown in any one of formulas I-III, a pharmaceutically acceptable salt or prodrug thereof, a solvate thereof, a hydrate thereof, a polymorphic substance thereof, a tautomer thereof, a stereoisomer thereof or an isotope substituted compound thereof, wherein n in the formulas I-III is an integer from 1 to 10, X is O, N or S, and Y is O, H2 or S. The bifunctional compound can effectively induce degradation of a core subunit of a PRC2 protein complex, so that cancers mediated by the PRC2 complex and subunits thereof including EZH2, EED, SUZ12, RbAp46 and RbAp48 are treated, and the carcinogenic activity of the subunits of the PRC2 complex is completely blocked.

Description

technical field [0001] The invention relates to the technical field of chemistry and medicine, in particular to a bifunctional compound capable of inducing the degradation of the core subunit of PRC2 protein complex, a pharmaceutical composition and its application. Background technique [0002] With the in-depth research on the pathogenesis of tumors, humans have deeply realized that the occurrence and development of tumors are not only related to DNA sequence changes caused by intracellular gene mutations or deletions, but also related to gene disorders caused by changes in other heritable substances , the so-called epigenetic phenomenon. Epigenetic modification can regulate processes such as proto-oncogene activation, tumor suppressor gene inactivation, DNA damage repair, and tumor stem cell differentiation through DNA methylation, histone modification, chromatin remodeling, or non-coding RNA interference. Thereby regulating the growth, development and pathological chang...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D405/14C07D401/14A61K31/496A61P35/00A61P35/02
CPCC07D405/14C07D401/14A61P35/00A61P35/02
Inventor 余洛汀刘志昊
Owner WEST CHINA HOSPITAL SICHUAN UNIV
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