药学学报, 2020, 55(11): 2491-2500
引用本文:
张旭, 蒙凌华. 源于天然产物或其衍生物的分子靶向抗肿瘤药物研究进展[J]. 药学学报, 2020, 55(11): 2491-2500.
ZHANG Xu, MENG Ling-hua. Progress in molecularly targeted anti-tumor drugs derived from natural products or their derivatives[J]. Acta Pharmaceutica Sinica, 2020, 55(11): 2491-2500.

源于天然产物或其衍生物的分子靶向抗肿瘤药物研究进展
张旭, 蒙凌华
中国科学院上海药物研究所, 上海 201203
摘要:
传统化疗药物、分子靶向药物和肿瘤免疫药物是目前用于肿瘤临床治疗的3类主要抗肿瘤药物。分子靶向抗肿瘤药物在分子水平上特异靶向在肿瘤细胞发生发展过程中的关键蛋白、基因或信号转导通路,从而选择性地杀伤肿瘤细胞或抑制其生长,具有选择性高、毒副作用小的特点,是目前抗肿瘤药物研究与开发的一个主流方向之一。天然产物是指动物、植物和微生物体内的化学成分或其代谢产物,其作为药物发现的一个重要来源,具有来源丰富和结构新颖多样的特点,目前已有多个来源于天然产物或其衍生物的分子靶向抗肿瘤药物用于肿瘤治疗或处于临床试验阶段。本文按照作用靶标分类对来源于天然产物或其衍生物的分子靶向抗肿瘤药物进行总结,并对各类药物的分子作用机制、研究进展和展望进行概述。
关键词:    分子靶向      抗肿瘤药物      药物发现      天然产物      衍生物     
Progress in molecularly targeted anti-tumor drugs derived from natural products or their derivatives
ZHANG Xu, MENG Ling-hua
Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China
Abstract:
Conventional chemotherapy drugs, molecularly targeted drugs, and immune checkpoint inhibitors are the major constituents of anti-tumor drugs in clinical settings at present. Molecularly targeted drugs specifically target the key proteins, genes, or signal transduction pathways in tumor cells which are essential for initiation and development of tumor, resulting in selective activity to induce cell death or growth inhibition. Molecularly targeted drugs have emerged as the mainstream in the research and development of anti-tumor drugs due to its high selectivity and low toxicity. Natural products refer to the chemical constituents or metabolites originated animals, plants, or microorganisms, which have been recognized as one of the important sources of drug discovery with abundant resources and diversified structures. At present, a number of molecularly targeted anti-tumor drugs derived from natural products or their derivatives have been approved for cancer therapy or in clinical trials. This review will summarize the molecularly targeted anti-tumor drugs derived from natural products or their derivatives according to their different cellular targets, and also outline the molecular mechanism, progress, and perspectives of these drugs.
Key words:    molecularly targeted    anti-tumor drug    drug discovery    natural product    derivative   
收稿日期: 2020-03-06
DOI: 10.16438/j.0513-4870.2020-0248
基金项目: 国家自然科学基金资助项目(81973345).
通讯作者: 蒙凌华,Tel:86-21-50801669,E-mail:lhmeng@simm.ac.cn
Email: lhmeng@simm.ac.cn
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参考文献:
[1] Harvey AL, Edrada-Ebel R, Quinn RJ. The re-emergence of natural products for drug discovery in the genomics era[J]. Nat Rev Drug Discov, 2015, 14:111-129.
[2] Hu HX, Wang XQ, Zhang H, et al. Mechanism and clinical progress of molecular tergeted cancer therapy[J]. Acta Pharm Sin (药学学报), 2015, 50:1232-1239.
[3] Hoelder S, Clarke PA, Workman P. Discovery of small molecule cancer drugs:successes, challenges and opportunities[J]. Mol Oncol, 2012, 6:155-176.
[4] Holohan C, Van Schaeybroeck S, Longley DB, et al. Cancer drug resistance:an evolving paradigm[J]. Nat Rev Cancer, 2013, 13:714-726.
[5] Newman DJ, Cragg GM. Natural products as sources of new drugs over the last 25 years[J]. J Nat Prod, 2007, 70:461-477.
[6] Dong ZJ, Han C, Liu JJ, et al. Histone deacetylase inhibitors:research advances[J]. J Int Pharm Res (国际药学研究杂志), 2017, 44:1098-1106, 1124.
[7] VanderMolen KM, McCulloch W, Pearce CJ, et al. Romidepsin (Istodax, NSC 630176, FR901228, FK228, depsipeptide):a natural product recently approved for cutaneous T-cell lymphoma[J]. J Antibiot (Tokyo), 2011, 64:525-531.
[8] Nakajima H, Kim YB, Terano H, et al. FR901228, a potent antitumor antibiotic, is a novel histone deacetylase inhibitor[J]. Exp Cell Res, 1998, 241:126-133.
[9] Grant C, Rahman F, Piekarz R, et al. Romidepsin:a new therapy for cutaneous T-cell lymphoma and a potential therapy for solid tumors[J]. Expert Rev Anticancer Ther, 2010, 10:997-1008.
[10] Kong F, Faulkner DJ. Leucettamol-A and leucettamol-B, 2 antimicrobial lipids from the calcareous sponge leucetta-microraphis[J]. J Org Chem, 1993, 58:970-971.
[11] Tsukamoto S, Takeuchi T, Rotinsulu H, et al. Leucettamol A:a new inhibitor of Ubc13-Uev1A interaction isolated from a marine sponge, Leucetta aff. microrhaphis[J]. Bioorg Med Chem Lett, 2008, 18:6319-6320.
[12] Macherla VR, Mitchell SS, Manam RR, et al. Structure-activity relationship studies of salinosporamide a (NPI-0052), a novel marine derived proteasome inhibitor[J]. J Med Chem, 2005, 48:3684-3687.
[13] Feling RH, Buchanan GO, Mincer TJ, et al. Salinosporamide A:a highly cytotoxic proteasome inhibitor from a novel microbial source, a marine bacterium of the new genus Salinospora[J]. Angew Chem Int Ed Engl, 2003, 42:355-357.
[14] Chauhan D, Hideshima T, Anderson KC. A novel proteasome inhibitor NPI-0052 as an anticancer therapy[J]. Br J Cancer, 2006, 95:961-965.
[15] Cragg GM, Newman DJ. Plants as a source of anti-cancer agents[J]. J Ethnopharmacol, 2005, 100:72-79.
[16] Sedlacek HH. Mechanisms of action of flavopiridol[J]. Crit Rev Oncol Hemat, 2001, 38:139-170.
[17] Senderowicz AM. Flavopiridol:the first cyclin-dependent kinase inhibitor in human clinical trials[J]. Invest New Drugs, 1999, 17:313-320.
[18] Byrd JC, Lin TS, Dalton JT, et al. Flavopiridol administered using a pharmacologically derived schedule is associated with marked clinical efficacy in refractory, genetically high-risk chronic lymphocytic leukemia[J]. Blood, 2007, 109:399-404.
[19] Schwartz GK, O'Reilly E, Ilson D, et al. Phase I study of the cyclin-dependent kinase inhibitor flavopiridol in combination with paclitaxel in patients with advanced solid tumors[J]. J Clin Oncol, 2002, 20:2157-2170.
[20] Karp JE, Smith BD, Levis MJ, et al. Sequential flavopiridol, cytosine arabinoside, and mitoxantrone:a phase II trial in adults with poor-risk acute myelogenous leukemia[J]. Clin Cancer Res, 2007, 13:4467-4473.
[21] Omura S, Iwai Y, Hirano A, et al. A new alkaloid AM-2282 of Streptomyces origin. Taxonomy, fermentation, isolation and preliminary characterization[J]. J Antibiot (Tokyo), 1977, 30:275-282.
[22] Tamaoki T, Nomoto H, Takahashi I, et al. Staurosporine, a potent inhibitor of phospholipid/Ca2+ dependent protein-kinase[J]. Biochem Biophys Res Commun, 1986, 135:397-402.
[23] Gani OA, Engh RA. Protein kinase inhibition of clinically important staurosporine analogues[J]. Nat Prod Rep, 2010, 27:489-498.
[24] Liu M, Jia H, Sha Y. Research progress in derivatization and structure-activity relationships of staurosporine[J]. J Shenyang Pharm Univ (沈阳药科大学学报), 2014, 31:224-240.
[25] Eastman A. Cell cycle checkpoints and their impact on anticancer therapeutic strategies[J]. J Cell Biochem, 2004, 91:223-231.
[26] Fuse E, Kuwabara T, Sparreboom A, et al. Review of UCN-01 development:a lesson in the importance of clinical pharmacology[J]. J Clin Pharmacol, 2005, 45:394-403.
[27] Sausville EA, Arbuck SG, Messmann R, et al. Phase I trial of 72-hour continuous infusion UCN-01 in patients with refractory neoplasms[J]. J Clin Oncol, 2001, 19:2319-2333.
[28] Gallogly MM, Lazarus HM. Midostaurin:an emerging treatment for acute myeloid leukemia patients[J]. J Blood Med, 2016, 7:73-83.
[29] Kindler T, Lipka DB, Fischer T. FLT3 as a therapeutic target in AML:still challenging after all these years[J]. Blood, 2010, 116:5089-5102.
[30] Levis M. Midostaurin approved for FLT3-mutated AML[J]. Blood, 2017, 129:3403-3406.
[31] Zhang J, Wang Q, Hou X, et al. Recent advances in cyclin-dependent kinase inhibitors with purine scaffold[J]. Chin J Org Chem (有机化学), 2015, 35:1022-1032.
[32] Benson C, Kaye S, Workman P, et al. Clinical anticancer drug development:targeting the cyclin-dependent kinases[J]. Br J Cancer, 2005, 92:7-12.
[33] MacCallum DE, Melville J, Frame S, et al. Seliciclib (CYC202, R-roscovitine) induces cell death in multiple myeloma cells by inhibition of RNA polymerase II-dependent transcription and down-regulation of Mcl-1[J]. Cancer Res, 2005, 65:5399-5407.
[34] Tolaney SM, Hilton JF, Cleary JM, et al. 2016 Annual Meeting of the American Society of Clinical Oncology (2016年美国肿瘤临床学会年会)[C]. Alexandria:AMER SOC CLINICAL ONCOLOGY Press, 2016:2503.
[35] Whitesell L, Mimnaugh EG, De Costa B, et al. Inhibition of heat shock protein HSP90-pp60v-src heteroprotein complex formation by benzoquinone ansamycins:essential role for stress proteins in oncogenic transformation[J]. Proc Natl Acad Sci U S A, 1994, 91:8324-8328.
[36] Liao ZY, Zhen YS. Advances in antitumor activity of the HSP90 inhibitor geldanamycin[J]. Acta Pharm Sin (药学学报), 2001, 36:716-720.
[37] Hostein I, Robertson D, DiStefano F, et al. Inhibition of signal transduction by the Hsp90 inhibitor 17-allylamino-17-demethoxygeldanamycin results in cytostasis and apoptosis[J]. Cancer Res, 2001, 61:4003-4009.
[38] Iyer G, Morris MJ, Rathkopf D, et al. A phase I trial of docetaxel and pulse-dose 17-allylamino-17-demethoxygeldanamycin in adult patients with solid tumors[J]. Cancer Chemother Pharmacol, 2012, 69:1089-1097.
[39] Jhaveri K, Taldone T, Modi S, et al. Advances in the clinical development of heat shock protein 90(Hsp90) inhibitors in cancers[J]. Biochim Biophys Acta, 2012, 1823:742-755.
[40] Modi S, Stopeck A, Linden H, et al. HSP90 inhibition is effective in breast cancer:a phase II trial of tanespimycin (17-AAG) plus trastuzumab in patients with HER2-positive metastatic breast cancer progressing on trastuzumab[J]. Clin Cancer Res, 2011, 17:5132-5139.
[41] Richardson PG, Chanan-Khan AA, Lonial S, et al. Tanespimycin and bortezomib combination treatment in patients with relapsed or relapsed and refractory multiple myeloma:results of a phase 1/2 study[J]. Br J Haematol, 2011, 153:729-740.
[42] Garcia-Carbonero R, Carnero A, Paz-Ares L. Inhibition of HSP90 molecular chaperones:moving into the clinic[J]. Lancet Oncol, 2013, 14:e358-e369.
[43] Pacey S, Wilson RH, Walton M, et al. A phase I study of the heat shock protein 90 inhibitor alvespimycin (17-DMAG) given intravenously to patients with advanced solid tumors[J]. Clin Cancer Res, 2011, 17:1561-1570.
[44] Siegel D, Jagannath S, Vesole DH, et al. A phase 1 study of IPI-504(retaspimycin hydrochloride) in patients with relapsed or relapsed and refractory multiple myeloma[J]. Leuk Lymphoma, 2011, 52:2308-2315.
[45] Riely GJ, Gettinger SN, Stoller RG, et al. 2011 Annual Meeting of the American Society of Clinical Oncology (2011年美国肿瘤临床学会年会)[C]. Alexandria:AMER SOC CLINICAL ONCOLOGY Press, 2011:7516.
[46] Powis G, Bonjouklian R, Berggren MM, et al. Wortmannin, a potent and selective inhibitor of phosphatidylinositol-3-kinase[J]. Cancer Res, 1994, 54:2419-2423.
[47] Sehgal SN. Sirolimus:its discovery, biological properties, and mechanism of action[J]. Transplant Proc, 2003, 35:7S-14S.
[48] Vignot S, Faivre S, Aguirre D, et al. mTOR-targeted therapy of cancer with rapamycin derivatives[J]. Ann Oncol, 2005, 16:525-537.
[49] Wang TT, Sathyamoorthy N, Phang JM. Molecular effects of genistein on estrogen receptor mediated pathways[J]. Carcinogenesis, 1996, 17:271-275.
[50] Papazisis KT, Zambouli D, Kimoundri OT, et al. Protein tyrosine kinase inhibitor, genistein, enhances apoptosis and cell cycle arrest in K562 cells treated with gamma-irradiation[J]. Cancer Lett, 2000, 160:107-113.
[51] Miltyk W, Craciunescu CN, Fischer L, et al. Lack of significant genotoxicity of purified soy isoflavones (genistein, daidzein, and glycitein) in 20 patients with prostate cancer[J]. Am J Clin Nutr, 2003, 77:875-882.
[52] Kumar NB, Krischer JP, Allen K, et al. A phase II randomized, placebo-controlled clinical trial of purified isoflavones in modulating steroid hormones in men diagnosed with localized prostate cancer[J]. Nutr Cancer, 2007, 59:163-168.
[53] Constantinou AI, Mehta R, Husband A. Phenoxodiol, a novel isoflavone derivative, inhibits dimethylbenz[a]anthracene (DMBA)-induced mammary carcinogenesis in female Sprague-Dawley rats[J]. Eur J Cancer, 2003, 39:1012-1018.
[54] Choueiri TK, Mekhail T, Hutson TE, et al. Phase I trial of phenoxodiol delivered by continuous intravenous infusion in patients with solid cancer[J]. Ann Oncol, 2006, 17:860-865.
[55] Goss G, Quinn M, Rutherford T, et al. A randomised phase II study of phenoxodiol with platinum or taxane chemotherapy in chemoresistant epithelial ovarian cancer, fallopian tube cancer and primary peritoneal cancer[J]. EJC Suppl, 2005, 3:261.
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