23届全国医药经济信息发布会-新药研发中结构优化策略-张健存课件.pptVIP

中科院广州生物医药与健康研究院 呼吸病国家重点实验室 张健存 jiancunzhang@ ;医药市场;Numbers of Drug Approved Since 1950;药物开发流程;新药 RD 的周期;先到化合物的发现;Lead Molecule;先导化合物结构优化 (1): Peptide;先导化合物结构优化 (2): TS mimetic;先导化合物结构优化 (3): Endogenous Substrate（天然底物）;Fast-Follower Approach 快速跟进策略;Fast Follower Approach Analyses;Fast Follower Strategies（策略）;Pharmacorphore and Auxophore 药效基团和辅助基团;Application of Auxophores;Application of Bioisosteres 等效基团的应用;Application of Bioisosteres;我们的研究领域;Novel Tyrosine Kinase Inhibitors as anticancer agents ;Tyrosine Kinase Inhibitors as Anticancer Agents;Tumor Genotype and TKIs;Tumor Genotype and TKIs-2;Approved Kinase Drugs;Structure, Target and Indications of Approved TKI Drugs-1;Structure, Target and Indications of Approved TKI Drugs-2;我们抗肿瘤领域研究的策略;;表皮生长因子受体(EGFR) ;EGFR Targeted Drugs;EGFR的活性口袋模型;Del-1 (E746-A750) and Del-2 (L747-T751) occur right after catalytic K745 and before helix C. This deletion will certainly interfere the salt bridge between K745 and E762 by either shifting the helix C position or changing the helix turn. Also in those deletions, the newly formed structure in this region has the potential to make contact with P-loop, and therefore change the P-loop conformation, (P-loop is a Gly rich loop and has extremely high mobility, and F723 in the P-loop make flip when the loop shifts and make new hydrophobic interactions. ; Japan US China* Iressa (TKI) 27.5% 10.4% ~40%？ mutations % 25.9% 1.8% 40.9% ;苯胺的4-位上容忍较大的取代基团，而且这种较大基团的存在，能够提高对HER2的抑制活性 ;基于药物分子辅助基团的结构修饰;EGFR激酶抑制筛选实验以及MTT肿瘤增长抑制细胞筛选表明我们的部分化合物展现出比IRESSA高20倍的生物抑制活性;人表皮样癌A431裸小鼠移植瘤的疗效;人表皮样癌A431裸小鼠移植瘤的疗效图;人表皮样癌A431裸小鼠移植瘤的照片;EGFR抑制剂小结;;Novel Dual Kinase Inhibitors双重抑制剂策略;Irreversible Kinase Inhibitors现有不可逆駱氨酸激酶抑制剂;可逆和不可逆抑制剂;不可逆抑制剂的优势;我们的研发策略;EGFR Inhibition(上皮生???因子受体抑制);Her2 Inhibition;an Irreversible Kinase Inhibitor;More Potent Cellular Activity;不可逆双重抑制剂小结;中国创新药物研究的优势;我国新药研发的不足;我国新药研发RD趋势?;谢谢 !