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百济神州AR靶向PROTAC专利公开《DEGRADATION OF ANDROGEN RECEPTOR (AR) BY CONJUGATION OF AR ANTAGONISTS WITH E3 LIGASE LIGAND AND METHODS OF USE》

 近日, 百济神州 公开了其双功能 AR PROTAC 降解剂专利公开,该专利( WO2021058017 )最早申请于2019年9月,通过招募E3泛素连接酶来降解AR。 化合物结构通式: 实施例结构摘取部分如下: 根据此前 Arvinas 报道: ARV-110 robustly degrades AR in all cell lines tested, with an observed halfmaximal degradation concentration (DC50) of ~1 nM . “ Proteolysis-targeting chimera (PROTAC) is a novel strategy for selective knockdown of target proteins by small molecules (Sakamoto KM et al., Proc Natl Acad Sci 2001, 98: 8554–9.; Sakamoto K.M. et al., Methods Enzymol. 2005; 399: 833‐847. ) . PROTAC utilizes the Ubiquitin‐protease system to target a specific protein and induce its degradation in the cell (Zhou P. et al., Mol Cell. 2000; 6 (3) : 751‐756; Neklesa T.K. et al., Pharmacol Ther. 2017; 174: 138‐144; Lu M. et al., Eur J Med Chem. 2018; 146: 251‐259; ) . The normal physiological function of the Ubiquitin-protease system is responsible for clearing denatured, mutated, or harmful proteins in cells. The normal physiological function of the Ubiquitin-protease system is responsible

百济神州《INHIBITORS OF KRAS G12C》专利公开

 近日,百济神州KRAS G12C抑制剂专利(WO2021058018)公开,专利最早申请于2019年9月,涉及KRAS G12C突变蛋白抑制剂,可用于治疗KRAS G12C介导的疾病。 此前已有 贝达药业 、 正大天晴 以及 加科思 等公司公开相关专利。 百济神州专利报道通式结构如下: 部分实施例结构如下: 体外IC50值结果如下: Example No. IC  50  (nM) Example No. IC  50  (nM) 1 3280 29 2.42 2 46000 30 15 3 23700 31 301 5 56.1 32 39.5 6 27.7 33 22.4 7 174 34 505 8 495 35 256 9 265 36 238 10 415 37 27.9 11 170 38 1570 12 379 40 1510 15 492 (P1) ; 5.27 (P2) 41 77.2 16 5650 (P1) ; 256 (P2) 42 9980 17 2200 (P1) ; 949 (P2) 44 9010 18 1560 45 12.6 19 976 46 172 20 2880 47 102 21 92.5 50 6.16 22 9.63 51 16.1 23 28.1 52 8.51 24 101 53 14.9 25 3.27 54 639 26 1080 55 <5.1 27 3720 56 941 28 178 ” RAS is one of the most well-known oncogene. In human, three RAS genes (HRAS, KRAS and NRAS) encode four highly homologous RAS proteins (HRAS, KRAS-4A, KRAS-4B and NRAS) . RAS proteins are small GTPases, they function as binary molecular switches that involved in transduction of extracellular growth and differentiation signaling. RAS generally cycles between a