【正文】 ly pathogeic in t9:Q22 (Ph+) CML/ALL ? Absence in normal tissues ? Modulate signal transduction events downstream Maintenance of chronic phase Adjunct to bone marrow transplantation bcrabl Fusion Protein bcr SH2 SH2 V SH2/SH3 kinase NT DNA Actin bcr autophosphorylation Phosphorylation of other substances McWhirter JR, EMBO 12:1533, 1993 bcr SH2 SH2 V SH2/SH3 kinase NT DNA Actin bcr Abl Tyrosine kinase Ras pathway JAKSTAT pathway PI3K pathway FAK Integrin Actin Paxillin Proliferation Transformation Adhesion Glivec bcr SH2 SH2 V SH2/SH3 kinase NT DNA Actin bcr Abl Tyrosine kinase Ras pathway JAKSTAT pathway PI3K pathway FAK Integrin Actin Paxillin Proliferation Transformation Adhesion Glivec Example Of “Rational” Approach: bcrabl directed agents O HO HN H C H OO HO HNH OO HC O 2 HH OH OO HO HO HO HN HC O 2 M eH N C NNH NC NN H 2NNNN H N HONNM eM eerbstatin lavendustin piceatannol AG957 AG1112 CGP 57148B = STI571 Natural product empiric lead 1st generation synthetic 2nd generation synthetic。 in clinic NEJM 344: 1031, 2022 Efficacy And Safety Of A Specific Inhibitor Of The Bcrabl Tyrosine Kinase In Chronic Myeloid Leukemia BRIAN ,.,MOSHE TALPAZ,.,DEBRA ,.,BIN PENG,., ELISABETH BUCHDUNGER,.,JOHN ,.,NICHOLAS ,.,HAGOP KANTARJIAN,., RENAUD CAPDEVILLE,.,SAYURI OHNOJONES,.,AND CHARLES ,. % in Metaphase 0 100 200 300 400 100 80 60 40 20 0 Ph Chromosome + Cells White Cell Count (cells x 103 / mm3 ) 0 30 60 90 120 150 100 10 1 Duration of Treatment with STI571 (Days) Growth factor receptor GF P I3 K Survival STAT3 Mitogenesis Src P P FAK Ras Promotes G1/S phase RhoGAP Migration Cell membrane Integrins Actin cytoskeleton Src激活的信號(hào)途徑 AP23464 PD166326 BMS354825 ? 口服小分子 bcrabl和 Src酪氨酸激酶抑制劑 ? 對(duì) Glivec耐藥的慢性粒細(xì)胞白血病、 PH+急性淋巴母細(xì)胞白血病有效 ? 最常見(jiàn)的副作用胃腸道反應(yīng)、發(fā)熱、虛弱、疲乏等 ? 主要的血液學(xué)指標(biāo)緩解率為 59% (95% CI: 49%, 68%) in AP, 32% (95% CI: 22%, 44%) in MB, 31% (95% CI: 18%, 47%) in LB, and 42% (95% CI: 26%, 59%) in Ph+ ALL. Dasatinib Growth Factor and Receptor Signal Transduction Pathways Growth Factor RTK RTK P P Active Inactive Proliferation S O S R A S R A F M A P K P Growth Factor Receptors Akt/PKB P I3 K P D K’s P PI4,5P2 P P PI3,4,5P3 GSK3 Apoptosis Survival PI3K Abl/Src P myc hTERT Immortalization 以端粒 /端粒酶為靶點(diǎn)的抗 腫瘤藥物研究 Telomere/Telomerase as targets ? Telomere cap ends of chromosomes ? Telomeric DNA contains binding sites for proteins ? Telomere binding proteins ? The plex limits telomere addition and keeps the ends from “fraying” Telomeric DNA contains simple tandem repeats Tetrahymena TTGGGG Vertebrates TTAGGG (TG)16TG23 ACGGATTTGATTAGGTATGTGGTGT ACGGATGTCTAACTTCTTGGTGT In many normal human adult cell types, telomerase is diminished Senescence Telomeres replenished by telomerase Telomerase Forced expression Finite replicative capacity Unlimited replicative capacity Cells keep dividing In 90% of human tumors, telomerase is strongly upregulated pared with normal cells Telomeres replenished by telomerase Cell division Telomerase: a telomeresynthesizing reverse transcriptase 5’ GTTAGGGTTAGGGTTAGGGTTA 3’ GAATCCC CAAUCCCAAUC 5’ 3’ Chromosome Terminus Protein TERT RNA TER Targeting the telomerase plex. hTR mutant siRNA Functions of Gquadruplexes ? Inpatible with telomerase attachment to the 3’ end ? Transcriptional regulation CMyc VEGF Bcl2 Kit PDGFA …… Telomere targeting agents (TTAs). Values are for potency in cell free assays to inhibit telomerase. NH O H 2 CM eNOOONON +C H 2 O HM eHH+ NN HN +NN +H NN+NH 3 CC H 3C H 3C H 3N H +NHN NH + H NH NNOO2,6 diamidoanthraquinone IC50 23uM TMPyT4 IC50 8uM BRACO19 ONNONSNONON ONONORH NNNN HRH 2 NN +N HN NH 2 NN HN +NHNNNNHN +N H 2NN +FFN NOOOC O O HFH 2 NTelomestatin IC50 Dibenzophenanthroline IC50 Ethidium derivative IC50 12459 triazine IC50 Pentacyclic acridine RHPS4 IC50 Fluoroquinophenoxazine 58 IC50 28uM Telomere targeting agents (TTAs). Values are for potency in cell free assays to inhibit telomerase. NH O H 2 CM eNOOONON +C H 2 O HM eHH+ NN HN +NN +H NN+NH 3 CC H 3C H 3C H 3N H +NHN NH + H NH NNOO2,6 diamidoanthraquinone IC50 23uM TMPyT4 IC50 8uM BRACO19 IC50 ONNONSNONON ONONORH NNNN HRH 2 NN +N HN NH 2 NN HN +NHNNNNHN +N H 2NN +FFN NOOOC O O HFH 2 NTelomestatin IC50 Dibenzophenanthroline IC50 Ethidium derivative IC50 12459 triazine IC50 Pentacyclic acridine RHPS4 IC50 Fluoroquinophenoxazine 58 IC50 28uM TMPyP4 ?Inhibit telomerase in a cellfree system and in cell lines ?Induce telomere shortening, crisis and apoptosis in myeloma cells ?Interact and stabilize imotif structures ?Inhibit cmyc and TERT expression ?Inhibit tumor growth in vivo Telomestatin ?A natural product from Streptomyces anulatus ?Inhibit telomerase activity ?Facilitate the formation of , or trap out preformed, Gquadruplex structures ?Disrupt the telomere maintenance and activate the DNA damageresponsible pathway (ATM, Chk2 , etc ) BRACO19 ?3,6,9tris