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

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. Inhibitor Lys 突变部位 EGFR Mutation Increase Iressa Sensitivity? Japan US China* Iressa (TKI) 27.5% 10.4% ~40%？ mutations % 25.9% 1.8% 40.9% J. Clin. Oncol., 21: 2237 Science 304: 1497-1500 *Qin et al, Cell Res (GIBH, CAS) EGFR Mutation Increase Iressa Sensitivity? 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 利用EGFR和HER2激酶ATP结合区边缘的Cys773和Cys805氨基酸残基上巯基具有较强的亲核性的特点，在药物分子中引入一个Michael加成受体，使药物分子能够与激酶形成共价键结合，达到不可逆抑制的目的。 Quinazoline SAR 基于药物分子辅助基团的结构修饰 Auxophore and Solvent interaction Modification site Iressa Over 100 new analogs made 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 Compound ID IC50 nM (U87MG) IC50 nM (A549) EGFR Kinase Assay（IC50） Iressa 20 20 80 nM Z509 1.2 14 120 nM Z546 1.5 19 15 nM Z580 20 20 90 nM Z582 1. 4 11 4 nM Z583 20 15 12 nM Z594 20 20 20 nM 体外药效 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 新化合物受体活性比易瑞沙提高近20倍 细胞抑制活性有近20倍提高 新化合物有很好的体内抑制活性（剂量调整中） 新化合物有较好的药物代谢及理化性质 EGFR/Her2 Dual Inhibitors Lapatinib is an approved EGFR/Her2 inhibitor for breast cancer Lapatinib has undesirable properties Too large dosage 1250 mg daily Limited efficacy Side effects Diarrhea Palmar-plantar erythrodysesthesia Nausea/vomiting, Rash, Fatigue Decreases in LVEF (possibly due to metabolites) Novel Dual Kinase Inhibitors双重抑制剂策略 Dual EGFR/Her2 both reversible and irreversible Small Molecule Inhibitor Overcome lapatinib liver toxicity Reduce dosage of lapatinib (potency and irre