Exploration of Receptor Tyrosine Kinase Inhibitor for Molecular Targeting Therapy

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研究生：	陳燕春 Chen, Yen Chun
論文名稱：	Exploration of Receptor Tyrosine Kinase Inhibitor for Molecular Targeting Therapy
指導教授：	許宗雄 Hseu, Tzong-Hsiung
口試委員:
學位類別：	博士 Doctor
系所名稱：	生命科學暨醫學院 - 生命科學系 Department of Life Sciences
論文出版年：	2010
畢業學年度：	98
語文別：	英文
論文頁數：	121
中文關鍵詞：	番瀉苷B 、骨肉瘤、血小板生長因子接受器、FLT3激酶接受器、急性骨髓性白血病
外文關鍵詞：	Sennoside B, Platelet-derived growth factor receptor, azulene, FMS-like tyrosine kinase 3, acute myeloid leukemia, osteosarcoma
相關次數：	點閱：1 下載：0
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分子標靶治療是以特定分子作為標靶的一種具選擇性的治療法。自癌細胞癌化的複雜機制逐漸明朗後，此種透過抑制癌細胞內的訊息傳遞，使癌細胞無法繼續進行分化、增殖、轉移及血管新生等步驟，成為最新的抗癌藥物開發方向；而切斷腫瘤細胞增生之訊息傳遞路徑的分子標靶治療的方法也已實現其救治某些癌症病患的理想，其中一個重要的藥物標靶即為受體型酪胺酸激酶。
正常細胞的酪胺酸激酶活性通常受到嚴密的調控，但是癌細胞內的酪胺酸激酶接受體往往過度表現或產生突變，很強的酪胺酸激酶活性，使得癌細胞不斷的進行分化、增殖、抗凋亡、血管新生以及轉移等。因此設法抑制酪胺酸激酶的活性，使酪胺酸激酶接受體不再過度表現，將有助於癌細胞的控制。受體型酪胺酸激酶常藉由配體或生長因子的刺激作為訊息傳遞的起點，以RAS、PI3K、AKT、MAPK等的酵素擔任訊息傳遞的工作；且主要藉由其磷酸化來完成訊息的傳遞，因此透過抑制細胞的受體激酶磷酸化，即可抑制癌症的發展，目前經過人體驗證的治療標靶已有數個，包括BCR-ABL, EGFR, Her2, VEGFR, PDGFR□, c-KIT等。
本研究透過天然物資源或設計的小分子開發分子標靶治療藥物，並探討其細胞機制為本研究之目的。除了透過癌細胞增殖抑制與蛋白質磷酸化抑制分析，來發掘這些可能抑制癌症發生的潛力分子並研究其分子機制，特別針對受體型酪胺酸激酶抑制劑的體外激酶抑制率、細胞激酶自體磷酸化抑制評估與體內動物之腫瘤抑制效果，證明天然分子或合成的分子中均能找到具激酶抑制活性的小分子，成為具藥效活性的潛力分子。本研究主要著重的藥效標靶為PDGFR□、FLT3；兩者同屬第三類受體型酪胺酸激酶家族，均藉由其磷酸化來完成訊息的傳遞，在癌細胞發展中佔有重要角色，前者與多種實質癌的發生有關，後者與血癌的發生相關。
實質癌的增長迅速，與腫瘤中血管新生關係密切，在腫瘤初形成時，癌細胞本身或周圍的結締組織，會分泌許多促使血管新生的物質，這些物質激活血管內皮細胞，造成腫瘤周圍結締組織的分解破壞、內皮細胞增生、內皮細胞的遷移與內皮細胞的重組形成新生血管。腫瘤的新生血管結構與正常血管差異很大，不僅管徑大小不一，角度任意彎曲，且缺乏完整的血管結構。PDGFR□存在分佈於血管的平滑肌細胞(vascular smooth muscle cells , VSMC)與周細胞(pericytes)，是重要的血管新生的訊號之一，而截斷腫瘤血管增生的訊號傳遞的癌症標靶治療藥物如sunitnib, sorafenib等，正是許多實質瘤的現行藥物治療方法。PDGFR除了在腫瘤血管的角色之外，也與組織纖維化的形成有關，而在某些腫瘤上也有基因突變或過度表達的情形，例如腸胃基質瘤與骨肉瘤的發生。在天然物番瀉苷B的分子機制研究中，發現番瀉苷B能透過與PDGF-BB與PDGFR之胞外區段之鍵結，能特異性的阻斷PDGF-BB的訊號傳遞而抑制了骨肉瘤細胞的增殖，可望成為具抗癌潛力的小分子。
急性骨髓性白血病的發生與FLT3的相關性在近幾年被瞭解，已知FLT3基因的突變會導致FLT3受體的活化，在30% 的AML病患會表現且預後不佳或容易復發，所以許多的研究嚐試利用FLT3的抑制劑控制血癌細胞的生長，目前FLT3抑制劑仍在進行臨床試驗驗證階段，可望成為輔助治療的藥物，在此研究中的藥物基團對FLT3的抑制效果佳，針對一系列的血癌細胞系呈現選擇性的抑制，其中藥效最佳的MV4-11即為表現FLT3-ITD的急性骨髓瘤細胞系，透過將MV4-11異種移殖的動物腫瘤模式，將候選化合物進行動物體內的藥效評估，發現能將腫瘤完全抑制。證明了小分子具有可口服吸收的特性，同時也證明其使用的安全性。
靶標藥物開發將是未來新藥開發的重要策略，因為靶標明確，藥物研發時間縮短，若能配合藥物基因組學的成果應用，更能對症下藥，使藥物更有效，安全性大大增高，針對標靶的選擇，也可發展適當的鷄尾酒療法，符合未來個人化醫療趨勢。本研究開發酪胺酸激酶抑制劑，發現天然物小分子番瀉苷B，透過細胞外的機制抑制PDGFR□ 的訊息傳遞，並抑制配體引致的細胞增生；另設計合成新的專利薁化合物小分子，在動物試驗能成功的抑制異體移植腫瘤的生長，而其兼具多重標靶的藥物特性，未來希望更進一步發展為人體用藥，成為癌症標靶治療藥物之一。

Molecular targeted therapy is a type of cancer treatment which attempts to interfere with specific molecules involved in the growth of cancer. Several drugs have been approved for certain types of cancer, including breast cancer, colon cancer, lung cancer, gastrointestinal stromal tumour and renal cell carcinoma. Base on the clinical application of targeted molecular therapy, the outcome shown more acceptable toxicity profiles than chemotherapy. It can be understood that the molecular targeted therapy drugs target the processes, pathways, and unique physiology which are particular to cancer cells, and thus they have the ability to reduce the cancer's destructive behavior.
These studies explore the receptor tyrosine kinase (RTK) inhibitor from natural and artificial synthesized compounds. Candidates screening from compound libraries which are highly effective in blocking kinase activity of RTKs in intact cells were picked out and used to evaluate their in vitro/in vivo antitumor efficiency. Both PDGFR□ and FLT3 belong to type III receptor tyrosine kinase. They have been identified to be related to some tumor formation in previous study. Aim to test the hypothesis of targeting therapy for sarcoma and acute myeloid leukemia with PDGFR and FLT3 inhibitors. The inhibition of cellular phosphorylation of PDGFR□ and FLT3 were verified in the presence exogenous growth factor. The most potent kinase inhibitor was picked out and identified as a druglike compound with good pharmaceutical properties, superior efficacy, and tolerability in a tumor xenograft model.
In conclusion, the sennoside B and novel azulenes have potential in RTK inhibition for cancer therapy. The novel compounds were screening for kinase inhibition, and the lead optimization generated from SAR study. More druglike molecules were discovered in the experimental stages. We hope that further clinical studies could be developed for cancer therapy and more or better molecular targeted drugs will become available in near future.

TABLE OF CONTENTS
中文摘要    I
ABSTRACT    IV
ACKNOWLEDGMENTS    VI
TABLE OF CONTENTS    VII
LIST OF TABLES    X
LIST OF FIGURES    XI
ABBREVIATIONS    XIII
CHAPTER 1. INTRODUCTION    1
1.1 SENNOSIDES    2
1.2 AZULENE COMPOUNDS    2
1.3 RECEPTOR TYROSINE KINASE IN CANCER    5
1.3.1 RECEPTOR TYROSINE KINASE    5
1.3.2 RECEPTOR TYROSINE KINASE IN CANCER    7
1.3.3 PLATELET DERIVED GROWTH FACTOR RECEPTOR (PDGFR)    8
1.3.4 FMS-LIKE TYROSINE KINASE 3 (FLT3)    11
1.4 MOLECULAR TARGETED CANCER THERAPY    16
1.5 AIMS OF THE STUDY    23
CHAPTER 2. EXTRACELLULAR RECEPTOR TYROSINE KINASE INHIBITOR: SENNOSIDE B INHIBITS PDGFR SIGNALING AND CELL PROLIFERATION INDUCED BY PDGF-BB IN HUMAN OSTEOSARCOMA CELLS    25
2.1 ABSTRACT    26
2.2 INTRODUCTION    27
2.3 MATERIALS AND METHODS    29
2.3.1 MATERIALS    29
2.3.2 OSTEOSARCOMA CELL CULTURE    30
2.3.3 CELL LYSATE PREPARATION AND WESTERN BLOT ANALYSIS    31
2.3.4 DOT BINDING ASSAY    32
2.3.5 CELL PROLIFERATION ASSAYS    32
2.3.6 STATISTICAL ANALYSIS    33
2.4 RESULTS    33
2.4.1 SENNOSIDE B SELECTIVELY INHIBITS PDGF-BB-INDUCED PDGFR PHOSPHORYLATION IN OSTEOSARCOMA CELLS    34
2.4.2 SENNOSIDE B BINDS TO THE PDGF-BB AND PDGFR EXTRACELLULAR DOMAINS    37
2.4.3 PDGF-BB-INDUCED PHOSPHORYLATION OF PDGFR-Β, STAT-5, AKT, AND ERK INHIBITION BY SENNOSIDE B    41
2.4.4 SENNOSIDE B SLOWS THE RATE OF PDGFR-Β ACTIVATION    44
2.4.5 SENNOSIDE B INHIBITS OSTEOSARCOMA CELL PROLIFERATION INDUCED BY PDGF-BB    46
2.5 DISCUSSION    51
2.6 CONCLUSIONS    55
CHAPTER 3. INTRACELLULAR RECEPTOR TYROSINE KINASE INHIBITOR: NOVEL AZULENE-BASED DERIVATIVES AS POTENT INHIBITORS OF FLT3 TYROSINE KINASE    57
3.1 ABSTRACT    58
3.2 INTRODUCTION    58
3.3 MATERIALS AND METHODS    64
3.3.1 CHEMISTRY    64
3.3.2 MOLECULAR MODELING AND DOCKING SIMULATION    68
3.3.3 IN VITRO KINASE ASSAYS    68
3.3.4 CELL PROLIFERATION ASSAYS    69
3.3.5 WESTERN BLOT ANALYSIS    74
3.3.6 FLOW CYTOMETRY    75
3.3.7 IN VIVO PHARMACOKINETICS    75
3.3.8 IN VIVO XENOGRAFT TUMOR MODEL    76
3.4 RESULTS    77
3.4.1 CHEMISTRY    77
3.4.2 MOLECULAR MODELING AND DOCKING SIMULATION    79
3.4.3 IN VITRO KINASE ASSAYS    81
3.4.4 COMPOUND 22 POTENTIALLY INHIBITS ACUTE MYELOID LEUKEMIA CELL LINES WITH FLT3-ITD MUTATION.    87
3.4.5 COMPOUND 22 INHIBITS FLT3/STAT5, FLT3/AKT SIGNALING PATHWAY IN MV4-11 CELL LINES.    89
3.4.6 COMPOUND 22 ARREST MV4-11 CELL WITH ACCUMULATION IN SUB-G1 PHASE AT HIGH CONCENTRATION    96
3.4.7 IN VIVO PHARMACOKINETICS    98
3.4.8 IN VIVO XENOGRAFT TUMOR MODEL    100
3.5 DISCUSSION    104
3.6 CONCLUSIONS    105
REFERENCES    107
APPENDIX    119

LIST OF TABLES
TABLE 1-1. DRUG APPROVED FOR MOLECULAR TARGETED CANCER THERAPY     19
TABLE 1-2. OBJECTIVE RESPONSE RATES IN PATIENTS TO DIFFERENT KINASE INHIBITORS    21
TABLE 3-1. SAR AT THE X/R1 POSITION    83
TABLE 3-2. SAR OF X, Y, AND R    84
TABLE 3-3. VARIATION OF THE R MOIETY IN 4,5-DIFLUORO-OXINDOLE    86
TABLE 3-4. IN VITRO KINASE AND CELLULAR KINASE ASSAY OF COMPOUND 22    87
TABLE 3-5. CELL PROLIFERATION INHIBITION OF COMPOUND 22    88
TABLE 3-6. IN VIVO PHARMACOKINETIC PARAMETERS OF COMPOUND 22    99












LIST OF FIGURES
FIGURE 1-1. STRUCTURE OF SENNOSIDES AND THE INTERMEDIATES    3
FIGURE 1-2. FOLLOW THE (HETERO)ARYLIDENE-2-OXINDOLE DERIVATIVES DESIGN    4
FIGURE 1-3. SAR STUDY OF AZULENE COMPOUNDS    4
FIGURE 1-4. RECEPTOR TYROSINE KINASES (20 FAMILIES)    6
FIGURE 1-5. PDGF–PDGFR INTERACTIONS    9
FIGURE 1-6. PDGF SIGNALING (MODIFIED FROM ROBERTSON ET AL. 2000)    9
FIGURE 1-7. PDGF RECEPTORS: MUTATIONS FOUND IN DIFFERENT CANCERS ARE DEPICTED    10
FIGURE 1-8. THE FLT3-ITD SIGNALING PATHWAYS (ZHOU ET AL. 2009)    13
FIGURE 1-9. FLT3 MUTATION IN AML    14
FIGURE 1-10. TWO-HIT MODEL FOR AML    16
FIGURE 2-1. PDGFR PHOSPHORYLATION IN MG63 CELLS TREATED WITH PDGF-BB AND SENNOSIDES A AND B    36
FIGURE 2-2. DOT-BINDING ASSAY OF THE INTERACTION BETWEEN PDGF-BB AND PDGFR EXTRACELLULAR DOMAIN WITH IMMOBILIZED SENNOSIDE B    39
FIGURE 2-3. EFFECTS OF SENNOSIDE B ON SIGNALING INDUCED BY PDGF-BB, EGF AND FBS IN MG63 CELLS    43
FIGURE 2-4. TIME COURSE AND CONCENTRATION-DEPENDENCE OF SENNOSIDE B DOWN-REGULATION OF PDGFR-Β PHOSPHORYLATION IN MG63 CELLS    45
FIGURE 2-5. PDGFR PHOSPHORYLATION IN OSTEOSACOMA CELLS TREATED WITH PDGF-BB AND SENNOSIDES B    48
FIGURE 2-6. SENNOSIDE B INHIBITION OF OSTEOSARCOMA CELL METABOLISM AND PROLIFERATION INDUCED BY PDGF-BB    50
FIGURE 3-1. NOVEL AZULENE-BASED COMPOUNDS    60
FIGURE 3-2. THE RATIONALE OF MEDICINAL CHEMISTRY FOR  AZULENE -OXINDOLES    60
FIGURE 3-3. STRUCTURES OF KNOWN FLT3 INHIBITORS    63
FIGURE 3-4. ESTABLISHED 32D/FLT3-WT, 32D/FLT3-ITD STABLE CLONES (UNPUBLISHED DATA BY DR. L. M. WANG & DR. C. H. KO)    73
FIGURE 3-5. EXAMPLES OF DESIGNED AND SYNTHSIZED AZULENE-OXINDOLE (UNPUBLISHED DATA BY DR. O. LEE & MR. C. H. CHEN)    78
FIGURE 3-6. MOLECULAR MODELING AND DOCKING SIMULATION (UNPUBLISHED DATA BY DR. T. S. CHEN)    80
FIGURE 3-7. COMPOUND 22 DOWN-REGULATION OF RECEPTOR TYROSINE KINASE PHOSPHORYLATION IN CELLS    92
FIGURE 3-8. EFFECTS OF COMPOUND 22 ON SIGNALING INDUCED BY FLT3 LIGAND IN RS4-11 CELLS    95
FIGURE 3-9. COMPOUND 22 ARREST MV4-11 CELL WITH ACCUMULATION IN SUB-G1 PHASE AT HIGH CONCENTRATION    97
FIGURE 3-10. COMPOUND 22 LEADS TO TUMOR REGRESSION IN MV4-11 XENOGRAFT NUDE MICE    101
FIGURE 3-11. COMPOUND 22 MODULATES FLT3 SIGNALING IN VIVO (UNPUBLISHED DATA BY DR. H. W. TSENG)    102
FIGURE 3-12. COMPOUND 22 INHIBITS TUMOR PROLIFERATION AND VASCULARIZATION IN VIVO (UNPUBLISHED DATA BY DR. H. W. TSENG)    103
SCHEME I. SYNTHESIS OF COMPOUNDS 12A AND 12B    66
SCHEME II. SYNTHESIS OF COMPOUNDS 16A-B, 22, AND 23    67

                                

Alvarez RH, Kantarjian HM, Cortes JE. Biology of platelet-derived growth factor and its involvement in disease. Mayo Clinic Proceedings 81(9), 1241-1257, 2006
Amadori S. New Agents for the Treatment of Acute Myeloid Leukemia. Midostaurin. Hematology Meeting Reports 2(5), 159-161, 2008
Andrae J, Gallini R, Betsholtz C. Role of platelet-derived growth factors in physiology and medicine. Genes & Development 22(10), 1276–1312, 2008
Bhalla K.N, George P, Gutti R, Bali P, Tao J, Guo F, Sigua C, Li Y, Cohen P, Atadja PA. A combination of histone deacetylase inhibitor LBH589 and the hsp90 inhibitor 17-AAG is highly active against human CML-BC and AML cells with constitutively active mutant FLT3 tyrosine kinase. J. Clin. Oncol. 2004, 22, 6541. (Post-meeting Edition).
Blaskovich MA, Lin Q, Delarue FL, Sun J, Park HS, Coppola D, Hamilton AD, Sebti AM. Design of GFB-111, a platelet-derived growth factor binding molecule with antiangiogenic and anticancer activity against human tumors in mice. Nature Biotechnology 18(10), 1065-1070, 2000
Board R, Jayson GC. Platelet-derived growth factor receptor (PDGFR): a target for anticancer therapeutics. Drug Resistance Updates: Reviews and Commentaries in Antimicrobial and Anticancer Chemotherapy 8(1-2), 75-83, 2005
Burnett AK, Knapper S. Targeting Treatment in AML. Hematology Am Soc Hematol Educ Program. 2007(1), 429-434, 2007
Cardenas C, Quesada AR, Medina MA. Evaluation of the anti-angiogenic effect of aloe-emodin. Cellular and Molecular Life Sciences 63(24), 3083-3089, 2006
Furet P, Bold G, Meyer T, Roesel J, Guagnano V. Aromatic Interactions with Phenylalanine 691and Cysteine 828. A Concept for FMS-like Tyrosine Kinase-3 Inhibition. Application to the Discovery of a New Class of Potential Antileukemia Agents. J. Med. Chem. 49(15), 4451-4454, 2006
Graves DT, Antoniades HN, Williams SR, Owen AJ. Evidence for functional platelet-derived growth factor receptors on MG-63 human osteosarcoma cells. Cancer Research 44(7), 2966-2970, 1984
George DJ, Dionne CA, Jani J, Angeles T, Murakata C, Lamb J, Isaas JT. Sustained in Vivo Regression of Dunning H Rat Prostate Cancers Treated with Combinations of Androgen Ablation and Trk Tyrosine Kinase Inhibitors, CEP-751 (KT-6587) or CEP-701 (KT-5555). Cancer Res. 59(10), 2395–2401, 1999
Gilliland, D G. Hematologic malignancies. Curr Opin Hematol. 8(4), 189-91, 2001
Griffith J, Black J, Faerman C, Swenson L, Wynn M, Lu F, Lippke J, Saxena K. The Structural Basis for Autoinhibition of FLT3 by the Juxtamembrane Domain. Molecular Cell 13(2), 169–178, 2004
Griswold IJ, Shen LJ, La Rose´e P, Demehi S, Heinrich MC, Braziel RM, McGreevey L, Haley AD, Giese N, Druker BJ, Deininger M. WN. Effects of MLN518, a Dual FLT3 and KIT Inhibitor, on Normal and Malignant Hematopoiesis. Blood 104(9), 2912-2918, 2004
Heldin CH, Johnsson A, Wennergren S, Wernstedt C, Betsholtz C, Westermark B. A human osteosarcoma cell line secretes a growth factor structurally related to a homodimer of PDGF A-chains. Nature 319(6), 511-514, 1986
Huang Q, Shen HM, Ong CN. Emodin inhibits tumor cell migration through suppression of the phosphatidylinositol 3-kinase-Cdc42/Rac1 pathway. Cellular and Molecular Life Sciences 62(10), 1167-1175, 2005
Hitoshi K, Yukimasa S, Kazutaka O, Satomi Y, Hiroshi K, Hiroshi U, Makiko S, Hitoshi A, Kenichi I, Shiro A and Tomoki N. Novel FLT3 Inhibitor FI-700 Selectively Suppresses the Growth of Leukemia Cells with FLT3 Mutations. Clin. Cancer Res. 13(15), 4575-4582, 2007
Huang Q, Lu G, Shen HM, Chung MC, Ong CN. Anti-cancer properties of anthraquinones from rhubarb. Medicinal Research Reviews 27(5), 609-630, 2007
Hubbard SR, Till JH. Protein tyrosine kinase structure and function. Annu Rev Biochem 69, 373-398, 2000
Hubbard SR, Miller WT. Receptor tyrosine kinases: mechanisms of activation and signaling. Curr Opin Cell Biol 19, 117-123, 2007
Jan C, Nicole M, Pascal F, Doriano F, Jennifer JC, James DG, Peter M and D. Gary G. Prediction of Resistance to Small Molecule FLT3 Inhibitors: Implications for Molecularly Targeted Therapy of Acute Leukemia. Cancer Res. 64(9), 6385-6389, 2004
Kaneshiro T, Morioka T, Inamine M, Kinjo T, Arakaki J, Chiba I, Sunagawa N, Suzui M, Yoshimi N. Anthraquinone derivative emodin inhibits tumor-associated angiogenesis through inhibition of extracellular signal-regulated kinase 1/2 phosphorylation. European Journal of Pharmacology 553(1-3), 46-53, 2006
Kim JH, Jin YR, Park BS, Kim TJ, Kim SY, Lim Y, Hong JT, Yoo HS, Yun YP. Luteolin prevents PDGF-BB-induced proliferation of vascular smooth muscle cells by inhibition of PDGF beta-receptor phosphorylation. Biochemical Pharmacology 69(12), 1715-1721, 2005
Knesl P, Röseling D and Jordis U. Improved Synthesis of Substituted 6,7-Dihydroxy-4-Quinazolineamines: Tandutinib, Erlotinib and Gefitinib. Molecules 11(4), 286-297, 2006
Lackey K, Cory M, Davis R, Frye SV, Harris PA, Hunter RN, Jung DK, McDonald OB, McNutt RW, Peel MR, Rutkowske RD, Veal JM, Wood ER. The discovery of potent cRaf1 kinase inhibitors. Bioorg. Med. Chem. Lett. 10(3), 223-226, 2000
Levitzki A. PDGF receptor kinase inhibitors for the treatment of PDGF driven diseases. Cytokine & Growth Factor Reviews 15(4), 229-235, 2004
Liang YC, Chen YC, Lin YL, Lin-Shiau SY, Ho CT, Lin JK. Suppression of extracellular signals and cell proliferation by the black tea polyphenol, theaflavin-3,3'-digallate. Carcinogenesis 20(4), 733-736, 1999
Lo HM, Hung CF, Tseng YL, Chen BH, Jian JS, Wu WB. Lycopene binds PDGF-BB and inhibits PDGF-BB-induced intracellular signaling transduction pathway in rat smooth muscle cells. Biochemical Pharmacology 74(1), 54-63, 2007
Lopes de Menezes DE, Peng J, Garrett EN, Louie SG, Lee SH, Wiesmann M, Tang Y, Shephard L, Goldbeck C, Oei Y, Ye H, Aukerman SL, Heise C. CHIR-258: A Potent Inhibitor of FLT3 Kinase in Experimental Tumor Xenograft Models of Human Acute Myelogenous Leukemia. Clin. Cancer Res. 11(14), 5281-5291, 2005
Lu Y, Zhang J, Qian J. The effect of emodin on VEGF receptors in human colon cancer cells. Cancer Biotherapy & Radiopharmaceuticals 23(2), 222-228, 2008
Madhusudan S. and Ganesan T S. Tyrosine kinase inhibitors in cancer therapy. Clinical Biochemistry 37(7), 618-635, 2004
Manning G, Whyte DB, Martinez R, Hunter T, Sudarsanam S. The protein kinase complement of the human genome. Science 298 (5600), 1912-1934, 2002
Markovic A, MacKenzie KL, Lock RB. FLT3: A new focus in the understanding of acute leukemia. Int. J. Biochem. Cell Biol. 37(6), 1168-1172, 2005
Mead AJ, Linch DC, Hills RK, Wheatley K, Burnett AK, Gale RE. FLT3 tyrosine kinase domain mutations are biologically distinct from and have a significantly more favorable prognosis than FLT3 internal tandem duplications in patients with acute myeloid leukemia. Blood 110(4), 1262-1270, 2007
Miknyoczki SJ, Chang H, Klein-Szanto A, Dionne CA, Ruggeri BA. The Trk Tyrosine Kinase Inhibitor CEP-701 (KT-5555) Exhibits Significant Antitumor Efficacy in Preclinical Xenograft Models of Human Pancreatic Ductal Adenocarcinoma. Clinical Cancer Res. 5(8), 2205–2212, 1999
Oefner C, D'Arcy A, Winkler FK, Eggimann B, Hosang M. Crystal structure of human platelet-derived growth factor BB. The EMBO Journal 11(11), 3921-3926, 1992
O’Farrell AM, Abrams TJ, Yuen HA, Ngai TJ, Louie SG., Yee KW, Wong LM, Hong W, Lee LB, Town A, Smolich BD, Manning WC, Murray LJ, Heinrich MC, Cherrington JM. SU11248 is a Novel FLT3 Tyrosine Kinase Inhibitor with Potent Activity in vitro and in vivo. Blood 101(9), 3597-3605, 2003
Panek RL, Lu GH, Klutchko SR, Batley BL, Dahring TK, Hamby JM, Hallak H, Doherty AM, Keiser JA. In vitro pharmacological characterization of PD 166285, a new nanomolar potent and broadly active protein tyrosine kinase inhibitor. The Journal of Pharmacology and Experimental Therapeutics 283(3), 1433-1444, 1997
Parcells BW, Ikeda AK, Simms-Waldrip T, Moore TB, Sakamoto KM. FMS-Like Tyrosine Kinase 3 in Normal Hematopoiesis and Acute Myeloid Leukemia. Stem Cells 24(5), 1174-1184, 2006
Paukku K, Valgeirsdottir S, Saharinen P, Bergman M, Heldin CH, Silvennoinen O. Platelet-derived growth factor (PDGF)-induced activation of signal transducer and activator of transcription (Stat) 5 is mediated by PDGF beta-receptor and is not dependent on c-src, fyn, jak1 or jak2 kinases. The Biochemical Journal 345(3), 759-766, 2000
Pecere T, Gazzola MV, Mucignat C, Parolin C, Vecchia FD, Cavaggioni A, Basso G, Diaspro A, Salvato B, Carli M, Palu G. Aloe-emodin is a new type of anticancer agent with selective activity against neuroectodermal tumors. Cancer Research 60(11), 2800-2804, 2000
Pietras K, Sjoblom T, Rubin K, Heldin CH, Ostman A. PDGF receptors as cancer drug targets. Cancer Cell 3(5), 439-443, 2003
Raymond JP, Christian AB, Jian L, Alan CG, Heidi O, Jennifer L and Mark R.P. Identification of 2-acylaminothiophene-3-carboxamides as potent inhibitors of FLT3. Bioorg. Med. Chem. Lett. 2006, 16(12), 3282.-3286, 2006
Robertson SC, Tynan JA, Donoghue DJ. RTK mutations and human syndromes-when good receptors turn bad. Trends in Genetics 16(6), 265–271, 2000
Sandy J, Davies M, Prime S, Farndale R. Signal pathways that transduce growth factor-stimulated mitogenesis in bone cells. Bone 23(1), 17-26, 1998
Schlessinger J. Cell signaling by receptor tyrosine kinases. Cell 103(2), 211-25, 2000
Shankar DB, Li J, Tapang P, Owen MJ, Pease LJ, Dai Y, Wei RQ, Albert DH, Bouska J J, Osterling DJ, Guo J, Marcotte PA, Johnson EF, Soni N, Hartandi K, Michaelides MR, Davidsen SK, Priceman SJ, Chang JC, Rhodes K, Shah N, Moore TB, Sakamoto K M, Glaser KB. ABT-869, a Multitargeted Receptor Tyrosine Kinase Inhibitor: Inhibition of FLT3 Phosphorylation and Signaling in Acute Myeloid Leukemia. Blood 109(8), 3400-3480, 2007
Sreenath VS, Daniel AH and Jeff S. Cell line-based platforms to evaluate the therapeutic efficacy of candidate anticancer agents. Nature reviews Cancer 10(4), 241-253, 2010
Srinivas G, Babykutty S, Sathiadevan PP, Srinivas P. Molecular mechanism of emodin action: transition from laxative ingredient to an antitumor agent. Medicinal Research Reviews 27(5), 591-608, 2007
Sun J, Wang DA, Jain RK, Carie A, Paquette S, Ennis E, Blaskovich MA, Baldini L, Coppola D, Hamilton AD, Sebti SM. Inhibiting angiogenesis and tumorigenesis by a synthetic molecule that blocks binding of both VEGF and PDGF to their receptors. Oncogene 24(29), 4701-4709, 2005
Tetsuo N, Toyonobu A, Masafumi Y, Hisamitu W, Toshio S, Masayoshi A. Formation and structure of 2-diazo-2,4-azulenequinone derivatives. J. Org. Chem. 60(18), 5919-5924, 1995
Thomas JE, Venugopalan M, Galvin R, Wang Y, Bokoch GM, Vlahos CJ. Inhibition of MG-63 cell proliferation and PDGF-stimulated cellular processes by inhibitors of phosphatidylinositol 3-kinase. Journal of Cellular Biochemistry 64(2), 182-195, 1997
Tove RA, Minna S, Goran A, and Karl A. Phenotypic modification of human osteosarcoma cells with the phorbol ester 1 2-O-tetradecanoylphorbol-1 3-acetate. Cell Growth & Differentiation 457(6), 457-464, 1995
Valgeirsdottir S, Paukku K, Silvennoinen O, Heldin CH, Claesson-Welsh L. Activation of Stat5 by platelet-derived growth factor (PDGF) is dependent on phosphorylation sites in PDGF beta-receptor juxtamembrane and kinase insert domains. Oncogene 16(4), 505-515, 1998
Vempati, S. The Roles of the Juxtamembrane Domain of FLT3-ITDs in Acute Myeloid leukemia. Thesis of University of Munich p4, 2007
Weber AA, Neuhaus T, Skach RA, Hescheler J, Ahn HY, Schror K, Ko Y, Sachinidis A. Mechanisms of the inhibitory effects of epigallocatechin-3 gallate on platelet-derived growth factor-BB-induced cell signaling and mitogenesis. The FASEB Journal 18(1), 128-130, 2004
Weisberg E, Boulton C, Kelly LM. Inhibition of Mutant FLT3 Receptors in Leukemia Cells by the Small Molecule Tyrosine Kinase Inhibitor PKC412. Cancer Cell 1(5), 433-43, 2002
Zhang H, Bajraszewski N, Wu E, Wang H, Moseman AP, Dabora SL, Griffin JD, Kwiatkowski DJ. PDGFRs are critical for PI3K/Akt activation and negatively regulated by mTOR. The Journal of Clinical Investigation 117(3), 730-738, 2007
Zhang L, Chang CJ, Bacus SS, Hung MC. Suppressed transformation and induced differentiation of HER-2/neu-overexpressing breast cancer cells by emodin. Cancer Research 55(17), 3890-3896, 1995
Zhang L, Lau YK, Xi L, Hong RL, Kim DS, Chen CF, Hortobagyi GN, Chang CJ, Hung MC. Tyrosine kinase inhibitors, emodin and its derivative repress HER-2/neu-induced cellular transformation and metastasis-associated properties. Oncogene 16(22), 2855-2863, 1998
Zhou J, Goh BC, Albert DH and Chen CS. ABT-869, a promising multi-targeted tyrosine kinase inhibitor: from bench to bedside. Journal of Hematology & Oncology 2, 33-46, 2009

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