Estrogen receptor protein degraders
A technology of estrogen receptors and ligands, applied in the field of estrogen receptor protein degradation agents, can solve problems such as limiting therapeutic effects
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Embodiment 1
[0251] Compound Synthesis and Characterization
[0252] general chemical method.
[0253] Unless otherwise stated, all purchased reagents were used as received without further purification. 1 HNMR and 13 C NMR spectra were recorded on a Bruker Advance 400 MHz spectrometer. 1 H NMR spectra are reported in parts per million (ppm) downfield of tetramethylsilane (TMS). all 13C NMR spectra are all reported in ppm and passed 1 H is obtained by decoupling. In reporting spectral data, the format (δ) chemical shift (multiplicity, J value (Hz), integral) is used with the following abbreviations: s = singlet, d = doublet, t = triplet, q = quartet Peak, m = multiplet. MS analysis was performed using a Waters UPLC-mass spectrometer. The final compounds were all purified by C18 reverse phase preparative HPLC column using solvent A (0.1% TFA in H 2 O) and solvent B (0.1% TFA in MeCN) as eluents. All final compounds were >95% pure by UPLC-MS.
[0254] The synthesis of the final com...
Embodiment 2
[0377] biometrics
[0378] cell culture. Human breast cancer cell line MCF-7 ( HTB-22 TM ) and T47D ( HTB-133 TM ) was purchased from the American Type Culture Collection (ATCC) in Manassas, Virginia, and cultured in Dulbecco's Modified Eagle's medium (DMEM ) cultured and maintained. Cells with 3–8 passages after purchase were used in the experiments as described.
[0379] Western blot analysis. Western blot analysis was performed essentially as previously described (Hu et al., 2015, PMID: 26358219). Cells treated with the indicated compounds were subjected to radioimmunoprecipitation assay protein lysis and extraction buffer (25 mmol / L Tris.HCl, pH 7.6, 150 mmol / L NaCl, 1% Nonidet P-40, 1% sodium deoxycholate and 0.1% sodium lauryl sulfate). After determination of protein concentration by BCA assay (Fisher Scientific, Pittsburgh, PA), equal amounts of total protein were electrophoresed through a 10% SDS-polyacrylamide gel. Separated protein bands were transferred ...
Embodiment 3
[0385] Biological test results
[0386] Representative compounds of the disclosure were evaluated for their ability to induce ER degradation in the MCF-7 ER+ breast cancer cell line, fulvestrant was used as a control.
[0387] Western blot data for compounds 12-15 as figure 1 shown. Representative compounds of the disclosure ranging from 3 to 9 atoms in linker length were evaluated for their ability to induce ER degradation in MCF-7 cells at concentrations of 1 nM, 10 nM and 100 nM, including compound 15, fulvestrant (5) , RAD1901 (9) and Raloxifene (1) served as controls. Western blot data such as figure 2 shown. Compounds 15, 18, 19, 20 and 21 with linkers comprising 6-9 carbon atoms were surprisingly effective at inducing ER degradation at concentrations as low as 1 nM.
[0388] evaluated with different R 3 The ability of representative compounds of the present disclosure of the group to induce ER degradation in MCF-7 cells at concentrations of 1 nM, 10 nM and 100 nM...
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