Generic placeholder image

Current Cancer Drug Targets


ISSN (Print): 1568-0096
ISSN (Online): 1873-5576

Review Article

Inhibitors and Activators of the p38 Mitogen-Activated MAP Kinase (MAPK) Family as Drugs to Treat Cancer and Inflammation

Author(s): William A. Denny*

Volume 22, Issue 3, 2022

Published on: 25 March, 2022

Page: [209 - 220] Pages: 12

DOI: 10.2174/1568009622666220215142837

Price: $65


The p38 MAP kinases are a sub-family of the broad group of mitogen-activated serinethreonine protein kinases. The best-characterised, most widely expressed, and most targeted by drugs is p38α MAP kinase. This review briefly summarises the place of p38α MAP kinase in cellular signalling and discusses the structures and activity profiles of representative examples of the major classes of inhibitors and activators (both synthetic compounds and natural products) of this enzyme. Primary screening was direct in vitro inhibition of isolated p38α enzyme.

Keywords: Kinase, p38MAPK, inhibitors, cancer, inflammation, review, activators.

Graphical Abstract
Cuenda, A.; Rousseau, S. p38 MAP-kinases pathway regulation, function and role in human diseases. Biochim. Biophys. Acta, 2007, 1773(8), 1358-1375.
[] [PMID: 17481747]
Zarubin, T.; Han, J. Activation and signaling of the p38 MAP kinase pathway. Cell Res., 2005, 15(1), 11-18.
[] [PMID: 15686620]
Canovas, B.; Nebreda, A.R. Diversity and versatility of p38 kinase signalling in health and disease. Nat. Rev. Mol. Cell Biol., 2021, 22(5), 346-366.
[] [PMID: 33504982]
Wagner, E.F.; Nebreda, A.R. Signal integration by JNK and p38 MAPK pathways in cancer development. Nat. Rev. Cancer, 2009, 9(8), 537-549.
[] [PMID: 19629069]
Braicu, C.; Buse, M.; Busuioc, C.; Drula, R.; Gulei, D.; Raduly, L.; Rusu, A.; Irimie, A.; Atanasov, A.G.; Slaby, O.; Ionescu, C.; Berindan-Neagoe, I. A comprehensive review on MAPK: A promising therapeutic target in cancer. Cancers (Basel), 2019, 11(10), 1618.
[] [PMID: 31652660]
Bühler, S.; Laufer, S.A. p38 MAPK inhibitors: A patent review (2012 - 2013). Expert Opin. Ther. Pat., 2014, 24(5), 535-554.
[] [PMID: 24611721]
Walter, N.M.; Wentsch, H.K.; Bührmann, M.; Bauer, S.M.; Döring, E.; Mayer-Wrangowski, S.; Sievers-Engler, A.; Willemsen-Seegers, N.; Zaman, G.; Buijsman, R.; Lämmerhofer, M.; Rauh, D.; Laufer, S.A. Design, Synthesis, and biological evaluation of novel type I1/2 p38α MAP kinase inhibitors with excellent selectivity, high potency, and prolonged target residence time by interfering with the R-spine. J. Med. Chem., 2017, 60(19), 8027-8054.
[] [PMID: 28834431]
Regan, J.; Pargellis, C.A.; Cirillo, P.F.; Gilmore, T.; Hickey, E.R.; Peet, G.W.; Proto, A.; Swinamer, A.; Moss, N. The kinetics of binding to p38MAP kinase by analogues of BIRB 796. Bioorg. Med. Chem. Lett., 2003, 13(18), 3101-3104.
[] [PMID: 12941343]
Campbell, R.M.; Anderson, B.D.; Brooks, N.A.; Brooks, H.B.; Chan, E.M.; De Dios, A.; Gilmour, R.; Graff, J.R.; Jambrina, E.; Mader, M.; McCann, D.; Na, S.; Parsons, S.H.; Pratt, S.E.; Shih, C.; Stancato, L.F.; Starling, J.J.; Tate, C.; Velasco, J.A.; Wang, Y.; Ye, X.S. Characterization of LY2228820 dimesylate, a potent and selective inhibitor of p38 MAPK with antitumor activity. Mol. Cancer Ther., 2014, 13(2), 364-374.
[] [PMID: 24356814]
Chen, R.; Qiao, Y.; Hu, W.; Cheng, Q.; Xie, H.; Zhou, L.; Xu, X.; Zheng, S.; Jiang, D. LY2228820 (ralimetinib) induces synergistic anti-cancer effects with anti-microtubule chemotherapeutic agents independent of P-glycoprotein in multidrug resistant cancer cells. Am. J. Cancer Res., 2019, 9, 2216-2232.
Vergote, I.; Heitz, F.; Buderath, P.; Powell, M.; Sehouli, J.; Lee, C.M.; Hamilton, A.; Fiorica, J.; Moore, K.N.; Teneriello, M.; Golden, L.; Zhang, W.; Pitou, C.; Bell, R.; Campbell, R.; Farrington, D.L.; Bell-McGuinn, K.; Wenham, R.M. A randomized, double-blind, placebo-controlled phase 1b/2 study of ralimetinib, a p38 MAPK inhibitor, plus gemcitabine and carboplatin versus gemcitabine and carboplatin for women with recurrent platinum-sensitive ovarian cancer. Gynecol. Oncol., 2020, 156(1), 23-31.
[] [PMID: 31791552]
Biau, J.; Thivat, E.; Chautard, E.; Stefan, D.; Boone, M.; Chauffert, B.; Bourgne, C.; Richard, D.; Molnar, I.; Levesque, S.; Bellini, R.; Kwiatkowski, F.; Karayan-Tapon, L.; Verrelle, P.; Godfraind, C.; Durando, X. Phase 1 trial of ralimetinib (LY2228820) with radiotherapy plus concomitant temozolomide in the treatment of newly diagnosed glioblastoma. Radiother. Oncol., 2021, 154, 227-234.
[] [PMID: 32976869]
Hoshi, T.; Watanabe Miyano, S.; Watanabe, H.; Sonobe, R.M.K.; Seki, Y.; Ohta, E.; Nomoto, K.; Matsui, J.; Funahashi, Y. Lenvatinib induces death of human hepatocellular carcinoma cells harboring an activated FGF signaling pathway through inhibition of FGFR-MAPK cascades. Biochem. Biophys. Res. Commun., 2019, 513(1), 1-7.
[] [PMID: 30944079]
Koyama, T.; Shimizu, T.; Iwasa, S.; Fujiwara, Y.; Kondo, S.; Kitano, S.; Yonemori, K.; Shimomura, A.; Iizumi, S.; Sasaki, T.; Furuse, J.; Yamamoto, N. First-in-human phase I study of E7090, a novel selective fibroblast growth factor receptor inhibitor, in patients with advanced solid tumors. Cancer Sci., 2020, 111(2), 571-579.
[] [PMID: 31797489]
Damjanov, N.; Kauffman, R.S.; Spencer-Green, G.T. Efficacy, pharmacodynamics, and safety of VX-702, a novel p38 MAPK inhibitor, in rheumatoid arthritis: Results of two randomized, double-blind, placebo-controlled clinical studies. Arthritis Rheum., 2009, 60(5), 1232-1241.
[] [PMID: 19404957]
Hill, R.J.; Dabbagh, K.; Phippard, D.; Li, C.; Suttmann, R.T.; Welch, M.; Papp, E.; Song, K.W.; Chang, K.C.; Leaffer, D.; Kim, Y-N.; Roberts, R.T.; Zabka, T.S.; Aud, D.; Dal Porto, J.; Manning, A.M.; Peng, S.L.; Goldstein, D.M.; Wong, B.R. Pamapimod, a novel p38 mitogen-activated protein kinase inhibitor: Preclinical analysis of efficacy and selectivity. J. Pharmacol. Exp. Ther., 2008, 327(3), 610-619.
[] [PMID: 18776065]
Cohen, S.B.; Cheng, T-T.; Chindalore, V.; Damjanov, N.; Burgos-Vargas, R.; Delora, P.; Zimany, K.; Travers, H.; Caulfield, J.P. Evaluation of the efficacy and safety of pamapimod, a p38 MAP kinase inhibitor, in a double-blind, methotrexate-controlled study of patients with active rheumatoid arthritis. Arthritis Rheum., 2009, 60(2), 335-344.
[] [PMID: 19180516]
Azevedo, R.; van Zeeland, M.; Raaijmakers, H.; Kazemier, B.; de Vlieg, J.; Oubrie, A. X-ray structure of p38α bound to TAK-715: Comparison with three classic inhibitors. Acta Crystallogr. D Biol. Crystallogr., 2012, 68(Pt 8), 1041-1050.
[] [PMID: 22868770]
Genovese, M.C.; Cohen, S.B.; Wofsy, D.; Weinblatt, M.E.; Firestein, G.S.; Brahn, E.; Strand, V.; Baker, D.G.; Tong, S.E.A. A 24-week, randomized, double-blind, placebo-controlled, parallel group study of the efficacy of oral SCIO-469, a p38 mitogen-activated protein kinase inhibitor, in patients with active rheumatoid arthritis. J. Rheumatol., 2011, 38(5), 846-854.
[] [PMID: 21285160]
Sokol, L.; Cripe, L.; Kantarjian, H.; Sekeres, M.A.; Parmar, S.; Greenberg, P.; Goldberg, S.L.; Bhushan, V.; Shammo, J.; Hohl, R.; Verma, A.; Garcia-Manero, G.; Li, Y-P.; Lowe, A.; Zhu, J.; List, A.F. Randomized, dose-escalation study of the p38α MAPK inhibitor SCIO-469 in patients with myelodysplastic syndrome. Leukemia, 2013, 27(4), 977-980.
[] [PMID: 23032694]
Appleby, J.R.G.; Humphries, L.A.; Blatcher, P.; Abu Khalil, A.; Kasparec, J.; Diederich, A.M.; Vernon, L.E.; Taggart, J.J.; Lloyd, R.S.; Spoors, P.G. Novel process of making pyrido pyrimidinone- 6-carboxylic acid derivatives and their use in the treatment of p38 kinase-mediated diseases. WO Patent 2007059500A2, 2007.
Singh, D.; Smyth, L.; Borrill, Z.; Sweeney, L.; Tal-Singer, R. A randomized, placebo-controlled study of the effects of the p38 MAPK inhibitor SB-681323 on blood biomarkers of inflammation in COPD patients. J. Clin. Pharmacol., 2010, 50(1), 94-100.
[] [PMID: 19880675]
Selness, S.R.; Devraj, R.V.; Devadas, B.; Walker, J.K.; Boehm, T.L.; Durley, R.C.; Shieh, H.; Xing, L.; Rucker, P.V.; Jerome, K.D.; Benson, A.G.; Marrufo, L.D.; Madsen, H.M.; Hitchcock, J.; Owen, T.J.; Christie, L.; Promo, M.A.; Hickory, B.S.; Alvira, E.; Naing, W.; Blevis-Bal, R.; Messing, D.; Yang, J.; Mao, M.K.; Yalamanchili, G.; Vonder Embse, R.; Hirsch, J.; Saabye, M.; Bonar, S.; Webb, E.; Anderson, G.; Monahan, J.B. Discovery of PH-797804, a highly selective and potent inhibitor of p38 MAP kinase. Bioorg. Med. Chem. Lett., 2011, 21(13), 4066-4071.
[] [PMID: 21641211]
Xing, L.; Devadas, B.; Devraj, R.V.; Selness, S.R.; Shieh, H.; Walker, J.K.; Mao, M.; Messing, D.; Samas, B.; Yang, J.Z.; Anderson, G.D.; Webb, E.G.; Monahan, J.B. Discovery and characterization of atropisomer PH-797804, a p38 MAP kinase inhibitor, as a clinical drug candidate. ChemMedChem, 2012, 7(2), 273-280.
[] [PMID: 22174080]
Hashem, H.M.A.; Mahrouse, M.A. In vitro metabolism study of a novel P38 kinase inhibitor: In silico predictions, structure elucidation using MS/MS-I. Future Med. Chem., 2018, 10(2), 201-220.
[] [PMID: 29239233]
MacNee, W.; Allan, R.J.; Jones, I.; De Salvo, M.C.; Tan, L.F. Efficacy and safety of the oral p38 inhibitor PH-797804 in chronic obstructive pulmonary disease: A randomised clinical trial. Thorax, 2013, 68(8), 738-745.
[] [PMID: 23539534]
Burnette, B.L.; Selness, S.; Devraj, R.; Jungbluth, G.; Kurumbail, R.; Stillwell, L.; Anderson, G.; Mnich, S.; Hirsch, J.; Compton, R.; De Ciechi, P.; Hope, H.; Hepperle, M.; Keith, R.H.; Naing, W.; Shieh, H.; Portanova, J.; Zhang, Y.; Zhang, J.; Leimgruber, R.M.; Monahan, J. SD0006: A potent, selective and orally available inhibitor of p38 kinase. Pharmacology, 2009, 84(1), 42-60.
[] [PMID: 19590255]
Walker, J.K.; Selness, S.R.; Devraj, R.V.; Hepperle, M.E.; Naing, W.; Shieh, H.; Kurambail, R.; Yang, S.; Flynn, D.L.; Benson, A.G.; Messing, D.M.; Dice, T.; Kim, T.; Lindmark, R.J.; Monahan, J.B.; Portanova, J. Identification of SD-0006, a potent diaryl pyrazole inhibitor of p38 MAP kinase. Bioorg. Med. Chem. Lett., 2010, 20(8), 2634-2638.
[] [PMID: 20227876]
Lee, M.R.; Dominguez, C. MAP kinase p38 inhibitors: Clinical results and an intimate look at their interactions with p38 alpha protein. Curr. Med. Chem., 2005, 12(25), 2979-2994.
[] [PMID: 16378500]
Basken, J.; Stuart, S.A.; Kavran, A.J.; Lee, T.; Ebmeier, C.C.; Old, W.M.; Ahn, N.G. Specificity of phosphorylation responses to mitogen activated protein (MAP) kinase pathway inhibitors in melanoma cells. Mol. Cell. Proteomics, 2018, 17(4), 550-564.
[] [PMID: 29255136]
Räsänen, K.; Dang, K.X.; Mustonen, H.; Ho, T.H.; Lintula, S.; Koistinen, H.; Stenman, U.H.; Haglund, C.; Stenman, J. MAPK inhibitors induce serine peptidase inhibitor Kazal type 1 (SPINK1) secretion in BRAF V600E-mutant colorectal adenocarcinoma. Mol. Oncol., 2018, 12(2), 224-238.
[] [PMID: 29193645]
Fu, H.; Cheng, L.; Jin, Y.; Cheng, L.; Liu, M.; Chen, L. MAPK inhibitors enhance HDAC inhibitor-induced redifferentiation in papillary thyroid cancer cells harboring BRAFV600E: An in vitro study. Mol. Ther. Oncolytics, 2019, 12, 235-245.
[] [PMID: 30847387]
Kopetz, S.; Grothey, A.; Yaeger, R.; Van Cutsem, E.; Desai, J.; Yoshino, T.; Wasan, H.; Ciardiello, F.; Loupakis, F.; Hong, Y.S.; Steeghs, N.; Guren, T.K.; Arkenau, H.T.; Garcia-Alfonso, P.; Pfeiffer, P.; Orlov, S.; Lonardi, S.; Elez, E.; Kim, T-W.; Schellens, J.H.M.; Guo, C.; Krishnan, A.; Dekervel, J.; Morris, V.; Calvo Ferrandiz, A.; Tarpgaard, L.S.; Braun, M.; Gollerkeri, A.; Keir, C.; Maharry, K.; Pickard, M.; Christy-Bittel, J.; Anderson, L.; Sandor, V.; Tabernero, J. Encorafenib, Binimetinib, and Cetuximab in BRAF V600E–mutated colorectal cancer. N. Engl. J. Med., 2019, 381(17), 1632-1643.
[] [PMID: 31566309]
Cuenda, A.; Rouse, J.; Doza, Y.N.; Meier, R.; Cohen, P.; Gallagher, T.F.; Young, P.R.; Lee, J.C. SB 203580 is a specific inhibitor of a MAP kinase homologue which is stimulated by cellular stresses and interleukin-1. FEBS Lett., 1995, 364(2), 229-233.
[] [PMID: 7750577]
Düzgün, S.A.; Yerlikaya, A.; Zeren, S.; Bayhan, Z.; Okur, E.; Boyacı, İ. Differential effects of p38 MAP kinase inhibitors SB203580 and SB202190 on growth and migration of human MDA-MB-231 cancer cell line. Cytotechnology, 2017, 69(4), 711-724.
[] [PMID: 28393288]
Sooman, L.; Lennartsson, J.; Gullbo, J.; Bergqvist, M.; Tsakonas, G.; Johansson, F.; Edqvist, P-H.; Ponten, F.; Jaiswal, A.; Navani, S.; Alafuzoff, A.; Popova, S.; Blomquist, E.; Ekmanet, S. Vandetanib combined with a p38 MAPK inhibitor synergistically reduces glioblastoma cell survival. Med. Oncol., 2013, 30(3), 638.
[] [PMID: 23783486]
Zhang, Z.; Wang, B.; Wu, S.; Wen, Y.; Wang, X.; Song, X.; Zhang, J.; Hou, L.; Chen, W. PD169316, a specific p38 inhibitor, shows antiviral activity against Enterovirus71. Virology, 2017, 508, 150-158.
[] [PMID: 28545002]
Seerden, J.P.; Leusink-Ionescu, G.; Leguijt, R.; Saccavini, C.; Gelens, E.; Dros, B.; Woudenberg-Vrenken, T.; Molema, G.; Kamps, J.A.; Kellogg, R.M. Syntheses and structure-activity relationships for some triazolyl p38α MAPK inhibitors. Bioorg. Med. Chem. Lett., 2014, 24(5), 1352-1357.
[] [PMID: 24508134]
Wadsworth, S.A.; Cavender, D.E.; Beers, S.A.; Lalan, P.; Schafer, P.H.; Malloy, E.A.; Wu, W.; Fahmy, B.; Olini, G.C.; Davis, J.E.; Pellegrino-Gensey, J.L.; Wachter, M.P.; Siekierka, J.J. RWJ 67657, a potent, orally active inhibitor of p38 mitogen-activated protein kinase. J. Pharmacol. Exp. Ther., 1999, 291(2), 680-687.
[] [PMID: 10525088]
Vinh, N.B.; Devine, S.M.; Munoz, L.; Ryan, R.M.; Wang, B.H.; Krum, H.; Chalmers, D.K.; Simpson, J.S.; Scammells, P.J. Design, synthesis, and biological evaluation of tetra-substituted thiophenes as inhibitors of p38α MAPK. ChemistryOpen, 2015, 4(1), 56-64.
[] [PMID: 25861571]
Bracht, C.; Hauser, D.R.J.; Schattel, V.; Albrecht, W.; Laufer, S.A. Synthesis and biological testing of N-aminoimidazole-based p38α MAP kinase inhibitors. ChemMedChem, 2010, 5(7), 1134-1142.
[] [PMID: 20473979]
Arai, T.; Ohno, M.; Inoue, H.; Hayashi, S.; Aoki, T.; Hirokawa, H.; Meguro, H.; Koga, Y.; Oshida, K.; Kainoh, M.; Suyama, K.; Kawai, H. Design and synthesis of novel p38α MAP kinase inhibitors: Discovery of pyrazole-benzyl ureas bearing 2-morpholinopyrimidine moiety. Bioorg. Med. Chem. Lett., 2012, 22, 5118-5122.
[] [PMID: 22749282]
Selness, S.R.; Devraj, R.V.; Monahan, J.B.; Boehm, T.L.; Walker, J.K.; Devadas, B.; Durley, R.C.; Kurumbail, R.; Shieh, H.; Xing, L.; Hepperle, M.; Rucker, P.V.; Jerome, K.D.; Benson, A.G.; Marrufo, L.D.; Madsen, H.M.; Hitchcock, J.; Owen, T.J.; Christie, L.; Promo, M.A.; Hickory, B.S.; Alvira, E.; Naing, W.; Blevis-Bal, R. Discovery of N-substituted pyridinones as potent and selective inhibitors of p38 kinase. Bioorg. Med. Chem. Lett., 2009, 19(20), 5851-5856.
[] [PMID: 19751974]
Tariq, S.; Kamboj, P.; Alam, O.; Amir, M. 1,2,4-Triazole-based benzothiazole/benzoxazole derivatives: Design, synthesis, p38α MAP kinase inhibition, anti-inflammatory activity and molecular docking studies. Bioorg. Chem., 2018, 81, 630-641.
[] [PMID: 30253336]
Somakala, K.; Tariq, S.; Amir, M. Synthesis, evaluation and docking of novel pyrazolo pyrimidines as potent p38α MAP kinase inhibitors with improved anti-inflammatory, ulcerogenic and TNF-α inhibitory properties. Bioorg. Chem., 2019, 87, 550-559.
[] [PMID: 30928877]
Petersen, L.K.; Blakskjær, P.; Chaikuad, A.; Christensen, A.B.; Dietvorst, J.; Holmkvist, J.; Knapp, S.; Kořínek, M.; Larsen, L.K.; Pedersen, A.E.; Röhm, S.; Sløk, F.A.; Hansen, N.J.V. Novel p38α map kinase inhibitors identified from yocto reactor DNA-encoded small molecule library. MedChemComm, 2016, 7, 1332-1339.
Röhm, S.; Berger, B-T.; Schröder, M.; Chaikuad, A.; Winkel, R.; Hekking, K.F.W.; Benningshof, J.J.C.; Müller, G.; Tesch, R.; Kudolo, M.; Forster, M.; Laufer, S.; Knapp, S. Fast iterative synthetic approach toward identification of novel highly selective p38 MAP kinase inhibitors. J. Med. Chem., 2019, 62(23), 10757-10782.
[] [PMID: 31702918]
Heo, J.; Shin, H.; Lee, J.; Kim, T.; Inn, K-S.; Kim, N-J. Synthesis and biological evaluation of N-cyclopropylbenzamide-benzophenone hybrids as novel and selective p38 mitogen activated protein kinase (MAPK) inhibitors. Bioorg. Med. Chem. Lett., 2015, 25(17), 3694-3698.
[] [PMID: 26115577]
Choi, M-S.; Heo, J.; Yi, C-M.; Ban, J.; Lee, N-J.; Lee, N-R.; Kim, S.W.; Kim, N-J.; Inn, K-S. A novel p38 mitogen activated protein kinase (MAPK) specific inhibitor suppresses respiratory syncytial virus and influenza A virus replication by inhibiting virus-induced p38 MAPK activation. Biochem. Biophys. Res. Commun., 2016, 477(3), 311-316.
[] [PMID: 27346133]
Gee, M.S.; Son, S.H.; Jeon, S.H.; Do, J.; Kim, N.; Ju, Y-J.; Lee, S.J.; Chung, E.K.; Inn, K-S.; Kim, N-J.; Lee, J.K. A selective p38α/β MAPK inhibitor alleviates neuropathology and cognitive impairment, and modulates microglia function in 5XFAD mouse. Alzheimers Res. Ther., 2020, 12(1), 45.
[] [PMID: 32317025]
Astolfi, A.; Kudolo, M.; Brea, J.; Manni, G.; Manfroni, G.; Palazzotti, D.; Sabatini, S.; Cecchetti, F.; Felicetti, T.; Cannalire, R.; Massari, S.; Tabarrini, O.; Loza, M.I.; Fallarino, F.; Cecchetti, V.; Laufer, S.A.; Barreca, M.L. Discovery of potent p38α MAPK inhibitors through a funnel like workflow combining in silico screening and in vitro validation. Eur. J. Med. Chem., 2019, 182, 111624.
[] [PMID: 31445234]
Park, J.B. In silico screening and in vitro activity measurement of javamide analogues as potential p38 MAPK inhibitors. Int. J. Mol. Sci., 2017, 18, 2704/1-2704/19.
Tariq, S.; Alam, O.; Amir, M. Synthesis, anti-inflammatory, p38α MAP kinase inhibitory activities and molecular docking studies of quinoxaline derivatives containing triazole moiety. Bioorg. Chem., 2018, 76, 343-358.
[] [PMID: 29227918]
Kaieda, A.; Takahashi, M.; Fukuda, H.; Okamoto, R.; Morimoto, S.; Gotoh, M.; Miyazaki, T.; Hori, Y.; Unno, S.; Kawamoto, T.; Tanaka, T.; Itono, S.; Takagi, T.; Sugimoto, H.; Okada, K.; Snell, G.; Bertsch, R.; Nguyen, J.; Sang, B.C.; Miwatashi, S. Structure-based design, synthesis, and biological evaluation of imidazo[4,5-b]pyridin-2-one-based p38 MAP kinase inhibitors: Part 1. ChemMedChem, 2019, 14(10), 1022-1030.
[] [PMID: 30945818]
Kaieda, A.; Takahashi, M.; Fukuda, H.; Okamoto, R.; Morimoto, S.; Gotoh, M.; Miyazaki, T.; Hori, Y.; Unno, S.; Kawamoto, T.; Tanaka, T.; Itono, S.; Takagi, T.; Sugimoto, H.; Okada, K.; Lane, W.; Sang, B.C.; Saikatendu, K.; Matsunaga, S.; Miwatashi, S. Structure-based design, synthesis, and biological evaluation of imidazo[4,5-b]pyridin-2-one-based p38 MAP kinase inhibitors: Part 2. ChemMedChem, 2019, 14(24), 2093-2101.
[] [PMID: 31697454]
Shah, N.G.; Tulapurkar, M.E.; Ramarathnam, A.; Brophy, A.; Martinez, R., III; Hom, K.; Hodges, T.; Samadani, R.; Singh, I.S.; MacKerell, A.D., Jr; Shapiro, P.; Hasday, J.D. Novel noncatalytic substrate-selective p38α-specific MAPK inhibitors with endothelial-stabilizing and anti-inflammatory activity. J. Immunol., 2017, 198(8), 3296-3306.
[] [PMID: 28298524]
Amin, K.M.; Syam, Y.M.; Anwar, M.M.; Ali, H.I.; Abdel-Ghani, T.M.; Serry, A.M. Synthesis and molecular docking studies of new furochromone derivatives as p38α MAPK inhibitors targeting human breast cancer MCF-7 cells. Bioorg. Med. Chem., 2017, 25(8), 2423-2436.
[] [PMID: 28291685]
Abdelhafez, O.M.; Ahmed, E.Y.; Latif, N.A.A.; Arafa, R.K.; Elmageed, Z.Y.A.; Ali, H.I. Design and molecular modeling of novel P38α MAPK inhibitors targeting breast cancer, synthesized from oxygen heterocyclic natural compounds. Bioorg. Med. Chem., 2019, 27, 1300-1319.
He, S.; Yang, J.; Hong, S.; Huang, H.; Zhu, Q.; Ye, L.; Li, T.; Zhang, X.; Wei, Y.; Gao, Y. Dioscin promotes prostate cancer cell apoptosis and inhibits cell invasion by increasing SHP1 phosphorylation and suppressing the subsequent MAPK signaling pathway. Front. Pharmacol., 2020, 11, 1099.
[] [PMID: 32792945]
Fu, R.; Zhang, L.; Li, Y.; Li, B.; Ming, Y.; Li, Z.; Xing, H.; Chen, J. Saikosaponin D inhibits autophagosome lysosome fusion and induces autophagy independent apoptosis in MDA MB 231 breast cancer cells. Mol. Med. Rep., 2020, 22(2), 1026-1034.
[] [PMID: 32468000]
Wang, Z.; Li, M.Y.; Zhang, Z.H.; Zuo, H.X.; Wang, J.Y.; Xing, Y.; Ri, M. yongHak; Ji, H.L.; Jin, C.H.; Xu, G.H.; Piao, L.X.; Jiang, C.G.; Ma, J.; Jin, X. Panaxadiol inhibits programmed cell death-ligand 1 expression and tumor proliferation via Hypoxia-Inducible Factor (HIF)-1α and STAT3 in human colon cancer cells. Pharmacol. Res., 2020, 155, 104727.
[] [PMID: 32113874]
Liu, Y.; Yang, H.; Guo, Q.; Liu, T.; Jiang, Y.; Zhao, M.; Zeng, K.; Tu, P. Cucurbitacin E inhibits Huh7 hepatoma carcinoma cell proliferation and metastasis via suppressing MAPKs and JAK/STAT3 pathways. Molecules, 2020, 25(3), 560.
[] [PMID: 32012950]
Velmurugan, B.K.; Lin, J-T.; Mahalakshmi, B.; Chuang, Y.C.; Lin, C.C.; Lo, Y-S.; Hsieh, M-J.; Chen, M-K. Luteolin-7-O-glucoside inhibits oral cancer cell migration and invasion by regulating matrix metalloproteinase-2 expression and extracellular signal-regulated kinase pathway. Biomolecules, 2020, 10(4), 502.
[] [PMID: 32224968]
Lv, W.L.; Liu, Q.; An, J-H.; Song, X-Y. Scutellarin inhibits hypoxia-induced epithelial-mesenchymal transition in bladder cancer cells. J. Cell. Physiol., 2019, 234(12), 23169-23175.
[] [PMID: 31127618]
Xiong, L.; Guo, W.; Yang, Y.; Gao, D.; Wang, J.; Qu, Y.; Zhang, Y. Tectoridin inhibits the progression of colon cancer through downregulating PKC/p38 MAPK pathway. Mol. Cell. Biochem., 2021, 476, 2729-2738.
Kong, Y.; Sun, W.; Wu, P. Hyperoside exerts potent anticancer activity in skin cancer. Front. Biosci., 2020, 25, 463-479.
[] [PMID: 31585897]
Wang, J-R.; Li, T-Z.; Wang, C.; Li, S-M.; Luo, Y-H.; Piao, X-J.; Feng, Y-C.; Zhang, Y.; Xu, W-T.; Zhang, Y.; Zhang, T.; Wang, S-N.; Xue, H.; Wang, H-X.; Cao, L.K.; Jin, C-H. Liquiritin inhibits proliferation and induces apoptosis in HepG2 hepatocellular carcinoma cells via the ROS-mediated MAPK/AKT/NF-κB signaling pathway. Naunyn Schmiedebergs Arch. Pharmacol., 2020, 393(10), 1987-1999.
[] [PMID: 31956937]
Li, Y.; Cheng, X.; Chen, C.; Huijuan, W.; Zhao, H.; Liu, W.; Xiang, Z.; Wang, Q. Apigenin, a flavonoid constituent derived from P. villosa, inhibits hepatocellular carcinoma cell growth by CyclinD1/CDK4 regulation via p38 MAPK-p21 signaling. Pathol. Res. Pract., 2020, 216(1), 152701.
[] [PMID: 31780054]
Hassan, A.H.E.; Yoo, S.Y.; Lee, K.W.; Yoon, Y.M.; Ryu, H.W.; Jeong, Y.; Shin, J-S.; Kang, S-Y.; Kim, S-Y.; Lee, H-H.; Park, B.Y.; Lee, K.T.; Lee, Y.S. Repurposing mosloflavone/5,6,7-trimethoxyflavone-resveratrol hybrids: Discovery of novel p38-α MAPK inhibitors as potent interceptors of macrophage-dependent production of proinflammatory mediators. Eur. J. Med. Chem., 2019, 180, 253-267.
[] [PMID: 31310917]
Panichpol, K.; Waterman, P.G. Novel flavonoids from the stem of Popowia Cauliflora. Phytochemistry, 1978, 17, 1363-1367.
Park, S.E.; Sapkota, K.; Kim, S.; Kim, H.; Kim, S.J. Kaempferol acts through mitogen-activated protein kinases and protein kinase B/AKT to elicit protection in a model of neuroinflammation in BV2 microglial cells. Br. J. Pharmacol., 2011, 164(3), 1008-1025.
[] [PMID: 21449918]
Hsu, Y-C.; Chiu, Y-T.; Lee, C-Y.; Wu, C-F.; Huang, Y-T. Anti-fibrotic effects of tetrandrine on bile-duct ligated rats. Can. J. Physiol. Pharmacol., 2006, 84(10), 967-976.
[] [PMID: 17218962]
Wu, S-H.; Chueh, F-S.; Chou, Y-C.; Ma, Y-S.; Peng, S-F.; Lin, C-C.; Liao, C-L.; Chen, P-Y.; Hsia, T-C.; Lien, J-C. Tetrandrine inhibits cell migration and invasion in human nasopharyngeal carcinoma NPC-TW 039 cells through inhibiting MAPK and RhoA signaling pathways. J. Food Biochem., 2020, 44, e13387.
[] [PMID: 32720324]
Erdogan, S.; Turkekul, K. Neferine inhibits proliferation and migration of human prostate cancer stem cells through p38 MAPK/JNK activation. J. Food Biochem., 2020, 44(7), e13253.
[] [PMID: 32394497]
Zhang, Q.; Wang, X.; Cao, S.; Sun, Y.; He, X.; Jiang, B.; Yu, Y.; Duan, J.; Qiu, F.; Kang, N. Berberine represses human gastric cancer cell growth in vitro and in vivo by inducing cytostatic autophagy via inhibition of MAPK/mTOR/p70S6K and Akt signaling pathways. Biomed. Pharmacother., 2020, 128, 110245.
[] [PMID: 32454290]
Yi, T.; Zhuang, L.; Song, G.; Zhang, B.; Li, G.; Hu, T. Akt signaling is associated with the berberine-induced apoptosis of human gastric cancer cells. Nutr. Cancer, 2015, 67(3), 523-531.
[] [PMID: 25837881]
Kwak, A.W.; Yoon, G.; Lee, M-H.; Cho, S-S.; Shim, J-H.; Chae, J-I. 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.
[] [PMID: 32629820]
Pei, X-D.; He, S-Q.; Shen, L-Q.; Wei, J-C.; Li, X-S.; Wei, Y-Y.; Zhang, Y-M.; Wang, X-Y.; Lin, F.; He, Z-L.; Jiang, L-H. 14,15β-dihydroxyklaineanone inhibits HepG2 cell proliferation and migration through p38MAPK pathway. J. Pharm. Pharmacol., 2020, 72(9), 1165-1175.
[] [PMID: 32419149]
Zhang, B.; Wang, X.; Cai, F.; Chen, W.; Loesch, U.; Bitzer, J.; Zhong, X.Y. Effects of salinomycin on human ovarian cancer cell line OV2008 are associated with modulating p38 MAPK. Tumour Biol., 2012, 33(6), 1855-1862.
[] [PMID: 22773373]
Ko, J-C.; Chen, J-C.; Chen, T-Y.; Yen, T-C.; Ma, P-F.; Lin, Y-C.; Wu, C.H.; Peng, Y.S.; Zheng, H.Y.; Lin, Y.W. Inhibition of thymidine phosphorylase expression by Hsp90 inhibitor potentiates the cytotoxic effect of salinomycin in human non-small-cell lung cancer cells. Toxicology, 2019, 417, 54-63.
[] [PMID: 30796972]

Rights & Permissions Print Cite
© 2024 Bentham Science Publishers | Privacy Policy