Raltitrexed thymidylate synthase inhibitor Hydroxycarbamide Ribonucleotide reductase inhibitor
Raltitrexed thymidylate synthase inhibitor Hydroxycarbamide Ribonucleotide reductase inhibitor pentostatin Adenosine deaminase inhibitor IV 治疗毛细胞白血病
EGFR inhibitors Gefitinib, Iressa (Astra. Zeneca) clog. P=4. 02; clog. Sw=-22 Phase II and Phase III results are not consistent personalized medicine (mutations common in Asians, women, and non-smokers) 减慢肿瘤细胞生长,抑制正常细 胞的代谢 TGF-a/EGF结合到无活性的EGFR homodimer/heterodimer Tyrosine Kinase cascade Overexpression of EGFR in solid tumors: 头颈、肺、 结肠直肠肿瘤 选择性:EGFR保护癌细胞远离细胞毒剂/放疗
埃罗替尼 Erlotinib, Tarceva clog. P=3. 92; clog. Sw=-4. 81 Pfizer合成,Roche/OST/Genentech研发 治疗NSCLC, 脑癌(罕用药) 耐受良好,EGFR普遍下调导致的副作用, 皮疹等 EGFR+患者中使用 Other targets: Personalized medicine VEGF(semaxanib), PDGFR, IGF-1 R, MET, SRC, Ras, AKT, STAT, PKB, etc.
Ras signal transduction inhibitors ~30% cancers start from Ras oncogene mutation;复发: 90%Ras 突变 ~50%结肠癌,~90%胰腺癌Ras基因点突变, ~39%骨髓瘤Ras突变 Mutant Ras patients survival median: 2. 1 yr,wt-Ras: 4 yr Ras (21 k. Da) belongs to Rat. Adeno-Sarcoma superfamily 膜结合的Ras蛋白分子 开关:细胞外配体刺 激受体RTK 受体 RTK二聚 Grb 2识别 作用于结合位点 recruit Sos Ras. GDP(inactive) to Ras. GTP Ras突变失去GTP酶活性,停留在Ras-GTP态,持 续发送信号到细胞核,导致肿瘤细胞不可控分化。 Ras结合到GFR膜内面发挥作用, Ras大量翻译后修饰:Ras Cterminal Caa. X (a=aliphatic, X = SMAQ) 法尼基化,切除aa. X,SFarnesyl-Cys的COOH甲基化,附 着到膜上
FTase Inhibitors Farnesyl pyrophosphate FPP Caa. X拟肽竞争F/CVFM: 体外抑 制,体内降解 FPP类似物:参与角鲨烯合酶等 途径,毒性? Tipifarnib(Janssen J&J,Phase III) 药效学研究:尽管法尼基蛋白被有效阻断, 与抗肿瘤活性无关联?? PI 3 K/AKT 2通路? 其它非Ras通路? Lonafarnib Indication: NSCLC
细胞周期抑制剂 Cyclin-dependent kinase, CDK 4/6作为细胞外信号的中心整合子,在G 1期磷酸化肿瘤 抑制蛋白p. Rb, 导致p. Rb失活。细胞周期蛋白D 1表达被Ras信号通路upregulated Flavopiridol 印度rohitukine植物碱半合成 Phase II终止 Olomoucine Cyclocel开发,phase II roscovitine 抑制剂竞争激酶的ATP结合位点 Cheng-Prusoff方程: Alsterpaullone 抗CDK 1, GSK-3, CDK 5 ? ? 细胞内ATP浓度 5~15 m. M; 衡量IC 50应考虑生理条件
m. TOR酶抑制剂 PI 3 K-m. TOR通路在>70%肿瘤中异常 结合FKBP 12蛋 白,抑制m. TOR 基因转录 增殖 血管内皮 生长因子 细胞生长 产生 Biomarker: p. S 6, p 4 E-BP 1, p. S 6 K ? ? 药物名 R 简述 Rapamycin H Wyeth抗排异 药,抗癌终止 AP 23573 -PO(CH 3)2 BC, GIST everolimus CH 2 OH Metastatic BC, PII temsirolimus COC(CH 3)(CH 2 OH)2 PIII, combo
Epigenetic protein families: a new frontier for drug discovery Nature Reviews Drug Discovery, 2012
Personalized Medicine Biomarker: 蛋白或核酸,在癌症中过度表达/突变 需较深入研究作用机理,决定癌症中关键的生物标记物 唾液、尿液、血液化验,质谱技术提高灵敏度 Genomics/proteomics研究 Cancer Genes Breast Cancer BRCA 1/2, ATM, HER 2 Burkitt’s lymphoma c-Myc Colorectal Cancer MLH 1, MSH 2/6, KRAS mutation Lung Cancer EGRF, HER 2/3/4 CML BRC-ABL Melanoma CDKN 2, BCL-2, BRAF V 600 E mutation endothelioma VEGFR, VEGFR 2 Others P 53, PKA, VEGFR 2, PDGFR More reading: R. Schilsky, “Personalized medicine in oncology: the future is now” Nature Reviews Drug Discovery, 2010
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