2021 / 03

Next Paper
DOI: 10.47183/mes.2021.033

REVIEW

Current trends in anticancer drug prototype in vitro pharmacology: bibliometric analysis 2019–2021

Ershov PV, Makarova AS
About authors

Centre for Strategic Planning and Management of Biomedical Health Risks of the Federal Medical Biological Agency, Moscow, Russia

Correspondence should be addressed: Pavel V. Ershov
Pogodinskaya, 10, korp 1, Moscow, 119121; ur.xobni@97levap

About paper

Author contribution: Ershov PV — literature search, manuscript writing and formatting, conceptualization of the paper; Makarova AS — literature search, manuscript editing.

Received: 2021-07-21 Accepted: 2021-08-18 Published online: 2021-09-27
|
  1. Kiriiri GK, Njogu PM, Mwangi AN. Exploring different approaches to improve the success of drug discovery and development projects: a review. Futur J Pharm Sci. 2020; 6: 27. DOI: 10.1186/ s43094-020-00047-9.
  2. Gibbs JB. Mechanism-based target identification and drug discovery in cancer research. Science. 2000; 287 (5460): 1969– 73. DOI: 10.1126/science.287.5460.1969.
  3. Druker BJ. Perspectives on the development of a molecularly targeted agent. Cancer Cell. 2002 Feb; 1 (1): 31–6. DOI: 10.1016/ s1535-6108(02)00025-9.
  4. Nam NH, Parang K. Current targets for anticancer drug discovery. Curr Drug Targets. 2003; 4 (2): 159–79. DOI: 10.2174/1389450033346966.
  5. Haider T, Pandey V, Banjare N, Gupta PN, Soni V. Drug resistance in cancer: mechanisms and tackling strategies. Pharmacol Rep. 2020; 72 (5): 1125–51. DOI:10.1007/s43440-020-00138-7.
  6. Devlin EJ, Denson LA, Whitford HS. Cancer treatment side effects: A meta-analysis of the relationship between response expectancies and experience. J Pain Symptom Manage. 2017; 54 (2): 245–58.e2. DOI:10.1016/j.jpainsymman.2017.03.017.
  7. Kumar B, Singh S, Skvortsova I, Kumar V. Promising targets in anti-cancer drug development: recent updates. Curr Med Chem. 2017; 24 (42): 4729–52. DOI: 10.2174/09298673246661703311 23648.
  8. Magalhaes LG, Ferreira LLG, Andricopulo AD. Recent advances and perspectives in cancer drug design. An Acad Bras Cienc. 2018; 90 (1 Suppl 2): 1233–50. DOI: 10.1590/00013765201820170823.
  9. Cui W, Aouidate A, Wang S, Yu Q, Li Y, Yuan S. Discovering anti-cancer drugs via computational methods. Front Pharmacol. 2020; 11: 733. DOI: 10.3389/fphar.2020.00733.
  10. Özen Çınar İ. Bibliometric analysis of breast cancer research in the period 2009–2018. Int J Nurs Pract. 2020; 26 (3): e12845. DOI:10.1111/ijn.12845.
  11. Didion CA, Henne WA. A bibliometric analysis of folate receptor research. BMC Cancer. 2020; 20 (1): 1109. DOI:10.1186/s12885020-07607-5.
  12. Jin B, Wu XA, Du SD. Top 100 most frequently cited papers in liver cancer: a bibliometric analysis. ANZ J Surg. 2020; 90 (1–2): 21–6. DOI:10.1111/ans.15414.
  13. Liu W, Wu L, Zhang Y, Shi L, Yang X. Bibliometric analysis of research trends and characteristics of oral potentially malignant disorders. Clin Oral Investig. 2020; 24 (1): 447–54. DOI: 10.1007/ s00784-019-02959-0.
  14. Van Eck NJ, Waltman L. Text mining and visualization using VOSviewer. ISSI Newsletter. 2011; 7 (3): 50–4.
  15. Tauno M, Jaak V. Clustvis: a web tool for visualizing clustering of multivariate data using Principal Component Analysis and heatmap. Nucleic Acids Research. 2015; 43 (W1): W566–W570, 2015. DOI: 10.1093/nar/gkv468.
  16. Arnst KE, Banerjee S, Chen H, Deng S, Hwang DJ, Li W, et al. Current advances of tubulin inhibitors as dual acting small molecules for cancer therapy. Med Res Rev. 2019; 39 (4): 1398– 426. DOI:10.1002/med.21568.
  17. Chopra B, Dhingra AK, Dhar KL, Nepali K. Emerging role of terpenoids for the treatment of cancer: a review. Mini Rev Med Chem. 2021. Available from: https://www.eurekaselect.com/190215/article. DOI: 10.2174/1389557521666210112143024.
  18. Kirsch P, Hartman AM, Hirsch AKH, Empting M. Concepts and сore principles of fragment-based drug design. Molecules. 2019; 24 (23): 4309. DOI: 10.3390/molecules24234309.
  19. Giacomini E, Rupiani S, Guidotti L, Recanatini M, Roberti M. The use of stilbene scaffold in medicinal chemistry and multi-target drug design. Curr Med Chem. 2016; 23 (23): 2439–89. DOI: 10.2 174/0929867323666160517121629.
  20. Hughes JP, Rees S, Kalindjian SB, Philpott KL. Principles of early drug discovery. Br J Pharmacol. 2011; 162 (6): 1239–49. DOI: 10.1111/j.1476-5381.2010.01127.x.
  21. Lipinski CA, Lombardo F, Dominy BW, Feeney PJ. Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. Adv Drug Deliv Rev. 1997; 23 (1–3): 3–25. DOI: 10.1016/S0169-409X(96)00423-1.
  22. Garcia da Silva AC, Rodrigues BDS, Andrade WM, Marques Dos Santos TR, de Carvalho FS, Sanz G, et al. Antiangiogenic and antitumoral activity of LQFM126 prototype against B16F10 melanoma cells. Chem Biol Interact. 2020; 325: 109127. DOI: 10.1016/j.cbi.2020.109127.
  23. Yamada K, Hori Y, Inoue S, Yamamoto Y, Iso K, Kamiyama H, et al. E7386, a selective inhibitor of the interaction between β-catenin and CBP, exerts antitumor activity in tumor models with activated canonical Wnt signaling. Cancer Res. 2021; 81 (4): 1052–62. DOI: 10.1158/0008-5472.CAN-20-0782.
  24. Zhang YF, Zhang ZH, Li MY, Wang JY, Xing Y, Ri M, et al. Britannin stabilizes T cell activity and inhibits proliferation and angiogenesis by targeting PD-L1 via abrogation of the crosstalk between Myc and HIF-1α in cancer. Phytomedicine. 2021; 81: 153425. DOI: 10.1016/j.phymed.2020.153425
  25. Yoon SH, Kim BK, Kang MJ, Im JY, Won M. Miconazole inhibits signal transducer and activator of transcription 3 signaling by preventing its interaction with DNA damage-induced apoptosis suppressor. Cancer Sci. 2020 Jul; 111 (7): 2499–507. DOI: 10.1111/cas.14432. Epub 2020 May 31. PMID: 32476221; PMCID: PMC7385363.
  26. Osmaniye D, Korkut Çelikateş B, Sağlık BN, Levent S, Acar Çevik U, Kaya Çavuşoğlu B, et al. Synthesis of some new benzoxazole derivatives and investigation of their anticancer activities. Eur J Med Chem. 2021; 210: 112979. DOI: 10.1016/j.ejmech.2020.112979.
  27. Zhang N, Wang J, Sheng A, Huang S, Tang Y, Ma S, et al. Emodin inhibits the proliferation of MCF-7 human breast cancer cells through activation of aryl hydrocarbon receptor (AhR). Front Pharmacol. 2021; 11: 622046. DOI: 10.3389/fphar.2020.622046.
  28. Qin J, Liu J, Wu C, Xu J, Tang B, Guo K, et al. Synthesis and biological evaluation of (3/4-(pyrimidin-2-ylamino) benzoyl)-based hydrazine-1 carboxamide/carbothioamide derivatives as novel RXRα antagonists. J Enzyme Inhib Med Chem. 2020; 35 (1): 880–96. DOI: 10.1080/14756366.2020.1740692.
  29. Zi CT, Yang L, Hu Y, Zhang P, Tang H, Zhang BL, et al. Synthesis, antitumor activity, and molecular docking of (-)-epigallocatechin3-gallate-4β-triazolopodophyllotoxin conjugates. J Asian Nat Prod Res. 2020: 1–9. DOI: 10.1080/10286020.2020.1786066.
  30. Huang WY, Zhang XR, Lyu L, Wang SQ, Zhang XT. Pyridazino[1,6-b]quinazolinones as new anticancer scaffold: synthesis, DNA intercalation, topoisomerase I inhibition and antitumor evaluation in vitro and in vivo. Bioorg Chem. 2020; 99: 103814. DOI: 10.1016/j.bioorg.2020.103814.
  31. Karatas E, Foto E, Ertan-Bolelli T, Yalcin-Ozkat G, Yilmaz S, Ataei S, et al. Discovery of 5-(or 6)-benzoxazoles and oxazolo[4,5-b]pyridines as novel candidate antitumor agents targeting hTopo IIα. Bioorg Chem. 2021; 112: 104913. DOI: 10.1016/j.bioorg.2021.104913.
  32. Fukuda T, Nanjo Y, Fujimoto M, Yoshida K, Natsui Y, Ishibashi F, et al. Lamellarin-inspired potent topoisomerase I inhibitors with the unprecedented benzo[g][1]benzopyrano[4,3-b]indol-6(13H)one scaffold. Bioorg Med Chem. 2019; 27 (2): 265–77. DOI: 10.1016/j.bmc.2018.11.037.
  33. Acar Çevik U, Sağlık BN, Osmaniye D, Levent S, Kaya Çavuşoğlu B, Karaduman AB, et al. Synthesis, anticancer evaluation and molecular docking studies of new benzimidazole-1,3,4oxadiazole derivatives as human topoisomerase types I poison. J Enzyme Inhib Med Chem. 2020; 35 (1): 1657–73. DOI: 10.1080/14756366.2020.1806831.
  34. Song Y, Feng S, Feng J, Dong J, Yang K, Liu Z, et al. Synthesis and biological evaluation of novel pyrazoline derivatives containing indole skeleton as anti-cancer agents targeting topoisomerase II. Eur J Med Chem. 2020; 200: 112459. DOI: 10.1016/j. ejmech.2020.112459.
  35. Al-Wahaibi LH, Gouda AM, Abou-Ghadir OF, Salem OIA, Ali AT, Farghaly HS, et al. Design and synthesis of novel 2,3-dihydropyrazino[1,2-a]indole-1,4-dione derivatives as antiproliferative EGFR and BRAFV600E dual inhibitors. Bioorg Chem. 2020; 104: 104260. DOI: 10.1016/j.bioorg.2020.104260.
  36. Eissa IH, Ibrahim MK, Metwaly AM, Belal A, Mehany ABM, Abdelhady AA, et al. Design, molecular docking, in vitro, and in vivo studies of new quinazolin-4(3H)-ones as VEGFR-2 inhibitors with potential activity against hepatocellular carcinoma. Bioorg Chem. 2021; 107: 104532. DOI: 10.1016/j.bioorg.2020.104532.
  37. Dai MD, Wang YL, Fan J, Dai Y, Ji YC, Sun YM, et al. DW14383 is an irreversible pan-FGFR inhibitor that suppresses FGFRdependent tumor growth in vitro and in vivo. Acta Pharmacol Sin. 2020. Available from: https://www.nature.com/articles/s41401020-00567-3. DOI: 10.1038/s41401-020-00567-3.
  38. Ahmed MF, Santali EY, El-Haggar R. Novel piperazine-chalcone hybrids and related pyrazoline analogues targeting VEGFR-2 kinase; design, synthesis, molecular docking studies, and anticancer evaluation. J Enzyme Inhib Med Chem. 2021; 36 (1): 307–18. DOI: 10.1080/14756366.2020.1861606.
  39. Zhuo LS, Wu FX, Wang MS, Xu HC, Yang FP, Tian YG, et al. Structure-activity relationship study of novel quinazoline-based 1,6-naphthyridinones as MET inhibitors with potent antitumor efficacy. Eur J Med Chem. 2020; 208: 112785. DOI: 10.1016/j. ejmech.2020.112785.
  40. Nan X, Zhang J, Li HJ, Wu R, Fang SB, Zhang ZZ, et al. Design, synthesis and biological evaluation of novel N-sulfonylamidinebased derivatives as c-Met inhibitors via Cu-catalyzed threecomponent reaction. Eur J Med Chem. 2020; 200: 112470. DOI: 10.1016/j.ejmech.2020.112470.
  41. Krishan S, Sahni S, Richardson DR. The anti-tumor agent, Dp44mT, promotes nuclear translocation of TFEB via inhibition of the AMPK-mTORC1 axis. Biochim Biophys Acta Mol Basis Dis. 2020; 1866 (12): 165970. DOI: 10.1016/j.bbadis.2020.165970.
  42. Cullen JK, Boyle GM, Yap PY, Elmlinger S, Simmons JL, Broit N, et al. Activation of PKC supports the anticancer activity of tigilanol tiglate and related epoxytiglianes. Sci Rep. 2021; 11 (1): 207. DOI: 10.1038/s41598-020-80397-9.
  43. Wagner E, Wietrzyk J, Psurski M, Becan L, Turlej E. Synthesis and anticancer evaluation of novel derivatives of isoxazolo[4,5-e] [1,2,4]triazepine derivatives and potential inhibitors of protein kinase C. ACS Omega. 2020; 6 (1): 119–34. DOI:10.1021/ acsomega.0c03801.
  44. Gilles P, Kashyap RS, Freitas MJ, Ceusters S, Van Asch K, Janssens A, et al. Design, synthesis and biological evaluation of pyrazolo[3,4-d]pyrimidine-based protein kinase D inhibitors. Eur J Med Chem. 2020; 205: 112638. DOI: 10.1016/j. ejmech.2020.112638.
  45. Sootome H, Miura A, Masuko N, Suzuki T, Uto Y, Hirai H, et al. Inhibitor TAS-119 enhances antitumor efficacy of taxanes in vitro and in vivo: preclinical studies as guidance for clinical development and trial design. Mol Cancer Ther. 2020; 19 (10): 1981–91. DOI: 10.1158/1535-7163.MCT-20-0036.
  46. Kar S, Ramamoorthy G, Mitra K, Shivalingegowda N, Mahesha, Mavileti SK, et al. Synthesis of novel spirobibenzopyrans as potent anticancer leads inducing apoptosis in HeLa cells. Bioorg Med Chem Lett. 2020; 30 (12): 127199. DOI: 10.1016/j. bmcl.2020.127199.
  47. Massaro M, Barone G, Barra V, Cancemi P, Di Leonardo A, Grossi G, et al. Pyrazole[3,4-d]pyrimidine derivatives loaded into halloysite as potential CDK inhibitors. Int J Pharm. 2021; 599: 120281. DOI: 10.1016/j.ijpharm.2021.120281.
  48. Ismail MI, Mohamady S, Samir N, Abouzid KAM. Design, synthesis, and biological evaluation of novel 7H-[1,2,4]triazolo[3,4-b][1,3,4] thiadiazine inhibitors as antitumor agents. ACS Omega. 2020; 5 (32): 20170–86. DOI: 10.1021/acsomega.0c01829.
  49. Zhang ZY, Dong SM, Liu YH, Zhang MM, Zhang JK, Zhu HJ, et al. Enhanced anticancer activity by the combination of vinpocetine and sorafenib via PI3K/AKT/GSK-3β signaling axis in hepatocellular carcinoma cells. Anticancer Drugs. 2021. Available from: https://journals.lww.com/anti-cancerdrugs/Abstract/2021/09000/Enhanced_anticancer_activity_by_the_ combination_of.7.aspx. DOI: 10.1097/CAD.0000000000001056.
  50. Zeytün E, Altıntop MD, Sever B, Özdemir A, Ellakwa DE, Ocak Z, et al. A new series of antileukemic agents: design, synthesis, in vitro and in silico evaluation of thiazole-based abl1 kinase inhibitors. Anticancer Agents Med Chem. 2021; 21 (9): 1099–109. DOI: 10.2174/1871520620666200824100408.
  51. Wang Y, Lv Z, Chen F, Wang X, Gou S. Discovery of 5-(3-chlorophenylamino) benzo[c][2,6] naphthyridine derivatives as highly selective ck2 inhibitors with potent cancer cell stemness inhibition. J Med Chem. 2021; 64 (8): 5082–98. DOI: 10.1021/ acs.jmedchem.1c00131.
  52. Yang H, Wang X, Wang C, Yin F, Qu L, Shi C et al. Optimization of WZ4003 as NUAK inhibitors against human colorectal cancer. Eur J Med Chem. 2021; 210: 113080. DOI: 10.1016/j. ejmech.2020.113080.
  53. Wu Q, Chen DQ, Sun L, Huan XJ, Bao XB, Tian CQ et al. Novel bivalent BET inhibitor N2817 exhibits potent anticancer activity and inhibits TAF1. Biochem Pharmacol. 2021; 185: 114435. DOI: 10.1016/j.bcp.2021.114435.
  54. Gan L, Gan Z, Dan Y, Li Y, Zhang P, Chen S, et al. Tetrazanbigen derivatives as peroxisome proliferator-activated receptor gamma (pparγ) partial agonists: design, synthesis, structure-activity relationship, and anticancer activities. J Med Chem. 2021; 64 (2): 1018–36. DOI: 10.1021/acs.jmedchem.0c01512.
  55. Zhang D, Sun G, Peng L, Tian J, Zhang H. Calycosin inhibits viability, induces apoptosis, and suppresses invasion of cervical cancer cells by upregulating tumor suppressor miR-375. Arch Biochem Biophys. 2020; 691: 108478. DOI: 10.1016/j. abb.2020.108478.
  56. Szczuka I, Wiśniewski J, Kustrzeba-Wójcicka I, Terlecki G. The effect of 3-bromopyruvate on the properties of cathepsin B in the aspect of metastatic potential of colon cancer cells. Adv Clin Exp Med. 2020; 29 (8): 949–57. DOI: 10.17219/acem/123622. PMID: 32820873.
  57. Ge Y, Yoon SH, Jang H, Jeong JH, Lee YM. Decursin promotes HIF-1α proteasomal degradation and immune responses in hypoxic tumour microenvironment. Phytomedicine. 2020; 78: 153318. DOI: 10.1016/j.phymed.2020.153318.
  58. Tabatabaei Dakhili SA, Pérez DJ, Gopal K, Haque M, Ussher JR, Kashfi K, et al. SP1-independent inhibition of FOXM1 by modified thiazolidinediones. Eur J Med Chem. 2021; 209: 112902. DOI: 10.1016/j.ejmech.2020.112902.
  59. Liu Y, Peng X, Li H, Jiao W, Peng X, Shao J, et al. STAT3 inhibitor napabucasin inhibits tumor growth and cooperates with proteasome inhibition in human ovarian cancer cells. Recent Pat Anticancer Drug Discov. 2021. DOI: 10.2174/157489281666621 0224155403.
  60. Wang X, Wu K, Fang L, Yang X, Zheng N, Du Z, et al. Discovery of N-substituted sulfamoylbenzamide derivatives as novel inhibitors of STAT3 signaling pathway based on Niclosamide. Eur J Med Chem. 2021; 218:113362. DOI: 10.1016/j.ejmech.2021.113362.
  61. Zhang J, Li C, Zhang L, Heng Y, Xu T, Zhang Y, et al. Andrographolide induces noxa-dependent apoptosis by transactivating atf4 in human lung adenocarcinoma cells. Front Pharmacol. 2021; 12: 680589. DOI:10.3389/fphar.2021.680589.
  62. Ibrahim TS, Hawwas MM, Taher ES, Alhakamy NA, Alfaleh MA, Elagawany M, et al. Design and synthesis of novel pyrazolo[3,4-d] pyrimidin-4-one bearing quinoline scaffold as potent dual PDE5 inhibitors and apoptotic inducers for cancer therapy. Bioorg Chem. 2020; 105: 104352. DOI: 10.1016/j.bioorg.2020.104352.
  63. Abosharaf HA, Diab T, Atlam FM, Mohamed TM. Osthole extracted from a citrus fruit that affects apoptosis on A549 cell line by histone deacetylasese inhibition (HDACs). Biotechnol Rep (Amst). 2020; 28: e00531. DOI: 10.1016/j.btre.2020.e00531.
  64. Xie Z, Wang F, Lin L, Duan S, Liu X, Li X, et al. An SGLT2 inhibitor modulates SHH expression by activating AMPK to inhibit the migration and induce the apoptosis of cervical carcinoma cells. Cancer Lett. 2020; 495: 200–10. DOI: 10.1016/j. canlet.2020.09.005.
  65. Watanabe S, Nishijima N, Hirai K, Shibata K, Hase A, Yamanaka T, et al. Anticancer activity of amb4269951, a choline transporter-like protein 1 inhibitor, in human glioma cells. Pharmaceuticals (Basel). 2020; 13 (5): 104. DOI: 10.3390/ph13050104.
  66. Hyun SY, Le HT, Min HY, Pei H, Lim Y, Song I, et al. Evodiamine inhibits both stem cell and non-stem-cell populations in human cancer cells by targeting heat shock protein 70. Theranostics. 2021; 11 (6): 2932–52. DOI: 10.7150/thno.49876.
  67. Tentori L, Dorio AS, Mazzon E, Muzi A, Sau A, Cuzzocrea S, et al. The glutathione transferase inhibitor 6-(7-nitro-2,1,3-benzoxadiazol4-ylthio)hexanol (NBDHEX) increases temozolomide efficacy against malignant melanoma. Eur J Cancer. 2011; 47(8): 1219–30. DOI: 10.1016/j.ejca.2010.12.008.
  68. Altamura G, Degli Uberti B, Galiero G, De Luca G, Power K, Licenziato L, et al. The small molecule BIBR1532 exerts potential anti-cancer activities in preclinical models of feline oral squamous cell carcinoma through inhibition of telomerase activity and downregulation of TERT. Front Vet Sci. 2021; 7: 620776. DOI: 10.3389/ fvets.2020.620776.
  69. Wang J, Iannarelli R, Pucciarelli S, Laudadio E, Galeazzi R, Giangrossi M, et al. Acetylshikonin isolated from Lithospermum erythrorhizon roots inhibits dihydrofolate reductase and hampers autochthonous mammary carcinogenesis in Δ16HER2 transgenic mice. Pharmacol Res. 2020; 161: 105123. DOI: 10.1016/j. phrs.2020.105123.
  70. Ding W, Zhang H, Mei G. Synergistic antitumor activity of DHA and JQ1 in colorectal carcinoma. Eur J Pharmacol. 2020; 885: 173500. DOI: 10.1016/j.ejphar.2020.173500.
  71. Yuan LW, Jiang XM, Xu YL, Huang MY, Chen YC, Yu WB, et al. Licochalcone A inhibits interferon-gamma-induced programmed death-ligand 1 in lung cancer cells. Phytomedicine. 2021; 80: 153394. DOI:10.1016/j.phymed.2020.153394.
  72. Boichuk S, Galembikova A, Bikinieva F, Dunaev P, Aukhadieva A, Syuzov K, et al. 2-APCAs, the novel microtubule targeting agents active against distinct cancer cell lines. Molecules. 2021; 26 (3): 616. DOI: 10.3390/molecules26030616.
  73. Lin S, Liang Y, Cheng J, Pan F, Wang Y. Novel diaryl-2H-azirines: Antitumor hybrids for dual-targeting tubulin and DNA. Eur J Med Chem. 2021; 214: 113256. DOI: 10.1016/j.ejmech.2021.113256.
  74. Sardaru MC, Craciun AM, Al Matarneh CM, Sandu IA, Amarandi RM, Popovici L, et al. Cytotoxic substituted indolizines as new colchicine site tubulin polymerisation inhibitors. J Enzyme Inhib Med Chem. 2020; 35 (1): 1581–95. DOI: 10.1080/14756366.2020.1801671.
  75. Li X, Liu Y, Zhao Y, Tian W, Zhai L, Pang H, et al. Rhein derivative 4f inhibits the malignant phenotype of breast cancer by downregulating Rac1 protein. Front Pharmacol. 2020; 11: 754. DOI: 10.3389/fphar.2020.00754.
  76. Yao Y, Yao QY, Xue JS, Tian XY, An QM, Cui LX, et al. Dexamethasone inhibits pancreatic tumor growth in preclinical models: Involvement of activating glucocorticoid receptor. Toxicol Appl Pharmacol. 2020; 401: 115118. DOI: 10.1016/j.taap.2020.115118.
  77. Wang SS, Zhang QL, Chu P, Kong LQ, Li GZ, Li YQ, et al. Synthesis and antitumor activity of α,β-unsaturated carbonyl moiety-containing oleanolic acid derivatives targeting PI3K/AKT/ mTOR signaling pathway. Bioorg Chem. 2020; 101: 104036. DOI: 10.1016/j.bioorg.2020.104036.
  78. Liu H, Li X, Duan Y, Xie JB, Piao XL. Mechanism of gypenosides of Gynostemma pentaphyllum inducing apoptosis of renal cell carcinoma by PI3K/AKT/mTOR pathway. J Ethnopharmacol. 2021; 271: 113907. DOI: 10.1016/j.jep.2021.113907.
  79. Li X, Zhao J, Yan T, Mu J, Lin Y, Chen J, et al. Cyanidin-3-Oglucoside and cisplatin inhibit proliferation and downregulate the PI3K/AKT/mTOR pathway in cervical cancer cells. J Food Sci. 2021. Available from: https://onlinelibrary.wiley. com/doi/10.1111/1750-3841.15740. DOI: 10.1111/17503841.15740.
  80. Ma W, Zhang Q, Li X, Ma Y, Liu Y, Hu S, et al. IPM712, a vanillin derivative as potential antitumor agents, displays better antitumor activity in colorectal cancers cell lines. Eur J Pharm Sci. 2020; 152: 105464. DOI: 10.1016/j.ejps.2020.105464.
  81. Han Y, Tian Y, Wang R, Fu S, Jiang J, Dong J, et al. Design, synthesis and biological evaluation of thieno[3,2-d]pyrimidine derivatives containing aroyl hydrazone or aryl hydrazide moieties for PI3K and mTOR dual inhibition. Bioorg Chem. 2020; 104: 104197. DOI: 10.1016/j.bioorg.2020.104197.
  82. Wang T, Wang J, Ren W, Liu ZL, Cheng YF, Zhang XM. Combination treatment with artemisinin and oxaliplatin inhibits tumorigenesis in esophageal cancer EC109 cell through Wnt/βcatenin signaling pathway. Thorac Cancer. 2020; 11 (8): 2316–24. DOI: 10.1111/1759-7714.13570.
  83. Gabata R, Harada K, Mizutani Y, Ouchi H, Yoshimura K, Sato Y, et al. Anti-tumor activity of the small molecule inhibitor PRI-724 against β-catenin-activated hepatocellular carcinoma. Anticancer Res. 2020; 40 (9): 5211–19. DOI: 10.21873/anticanres.14524.
  84. Shang FF, Wang JY, Xu Q, Deng H, Guo HY, Jin X, et al. Design, synthesis of novel celastrol derivatives and study on their antitumor growth through HIF-1α pathway. Eur J Med Chem. 2021; 220: 113474. Available from: https://www.sciencedirect. com/science/article/abs/pii/S0223523421003238?via%3Dihub. DOI: 10.1016/j.ejmech.2021.113474.
  85. Ge Y, Yoon SH, Jang H, Jeong JH, Lee YM. Decursin promotes HIF-1α proteasomal degradation and immune responses in hypoxic tumour microenvironment. Phytomedicine. 2020; 78: 153318. DOI:10.1016/j.phymed.2020.153318.
  86. Kang DY, Sp N, Lee JM, Jang KJ. Antitumor effects of ursolic acid through mediating the inhibition of STAT3/PD-L1 signaling in non-small cell lung cancer cells. Biomedicines. 2021; 9 (3): 297. DOI:10.3390/biomedicines9030297.
  87. Cui J, Li H, Wang Y, Tian T, Liu C, Wang Y, et al. Skullcapflavone I has a potent anti-pancreatic cancer activity by targeting miR-23a. Biofactors. 2020; 46 (5): 821–30. DOI: 10.1002/biof.1621.
  88. Houssein M, Abi Saab W, Khalil M, Khalife H, Fatfat M. Cell death by gallotannin is associated with inhibition of the JAK/STAT pathway in human colon cancer cells. Curr Ther Res Clin Exp. 2020; 92: 100589. DOI: 10.1016/j.curtheres.2020.100589.
  89. Luo W, Sun R, Chen X, Li J, Jiang J, He Y, et al. ERK activationmediated autophagy induction resists licochalcone a-induced anticancer activities in lung cancer cells in vitro. Onco Targets Ther. 2021; 13: 13437–50. DOI: 10.2147/OTT.S278268.
  90. Zhang WH, Chen S, Liu XL, Bing-Lin, Liu XW, Zhou Y. Study on antitumor activities of the chrysin-chromene-spirooxindole on Lewis lung carcinoma C57BL/6 mice in vivo. Bioorg Med Chem Lett. 2020; 30 (17): 127410. DOI: 10.1016/j.bmcl.2020.127410.
  91. Kwak AW, Yoon G, Lee MH, Cho SS, Shim JH, Chae JI. Picropodophyllotoxin, an epimer of podophyllotoxin, causes apoptosis of human esophageal squamous cell carcinoma cells through ROS-mediated JNK/P38 MAPK pathways. Int J Mol Sci. 2020; 21 (13): 4640. DOI: 10.3390/ijms21134640.
  92. Potočnjak I, Šimić L, Gobin I, Vukelić I, Domitrović R. Antitumor activity of luteolin in human colon cancer SW620 cells is mediated by the ERK/FOXO3a signaling pathway. Toxicol In Vitro. 2020; 66: 104852. DOI:10.1016/j.tiv.2020.104852.
  93. Brooks JD, Teraoka SN, Bernstein L, Mellemkjær L, Malone KE, Lynch CF, et al. Common variants in genes coding for chemotherapy metabolizing enzymes, transporters, and targets: a case-control study of contralateral breast cancer risk in the WECARE Study. Cancer Causes Control. 2013; 24 (8): 1605–14. DOI: 10.1007/s10552-013-0237-6.
  94. Bushweller JH. Targeting transcription factors in cancer — from undruggable to reality. Nat Rev Cancer. 2019; 19 (11): 611–24. DOI: 10.1038/s41568-019-0196-7.
  95. Lu H, Zhou Q, He J, Jiang Z, Peng C, Tong R, et al. Recent advances in the development of protein-protein interactions modulators: mechanisms and clinical trials. Signal Transduct Target Ther. 2020; 5 (1): 213. DOI: 10.1038/s41392-020-00315-3.
  96. Ivanov AA, Khuri FR, Fu H. Targeting protein-protein interactions as an anticancer strategy. Trends Pharmacol Sci. 2013; 34 (7): 393–400. DOI: 10.1016/j.tips.2013.04.007.
  97. Engin HB, Kreisberg JF, Carter H. Structure-based analysis reveals cancer missense mutations target protein interaction interfaces. PLoS One. 2016; 11 (4): e0152929. DOI: 10.1371/ journal.pone.0152929.
  98. Porta-Pardo E, Garcia-Alonso L, Hrabe T, Dopazo J, Godzik A. A pan-cancer catalogue of cancer driver protein interaction interfaces. PLoS Comput Biol. 2015; 11 (10): e1004518. DOI: 10.1371/journal.pcbi.1004518.
  99. Duffy MJ, Crown J. Drugging "undruggable" genes for cancer treatment: Are we making progress? Int J Cancer. 2021; 148 (1): 8–17. DOI: 10.1002/ijc.33197.
  100. Santos R, Ursu O, Gaulton A, Bento AP, Donadi RS, Bologa CG, et al. A comprehensive map of molecular drug targets. Nat Rev Drug Discov. 2017; 16 (1): 19–34. DOI: 10.1038/nrd.2016.230.