Generic placeholder image

Anti-Cancer Agents in Medicinal Chemistry

Editor-in-Chief

ISSN (Print): 1871-5206
ISSN (Online): 1875-5992

Research Article

Novel Potent EGFR-JAK3 Dual-Target Inhibitor that Overcomes KRAS Mutation Resistance in Colorectal Cancer

Author(s): Tingyu Wu, Jiawen Yu, Changyuan Wang, Yue Jin, Xu Zheng, Lixue Chen*, Xiaodong Ma* and Xiuli Sun*

Volume 23, Issue 4, 2023

Published on: 20 August, 2022

Page: [440 - 449] Pages: 10

DOI: 10.2174/1871520622666220609112816

Price: $65

Abstract

Background: In-depth and clear mechanistic study is a prerequisite for new drugs to enter clinical research.

Methods: New chemical entity BY4008 was identified by our lab as a novel and highly potent EGFR and JAK3 dualtarget inhibitor. A cell-based test exhibited strong antiproliferative activities against SW620 and HCT116 colon cancer cells harboring KRAS mutation with IC50 of nanomolar potency. Furthermore, acridine orange/ethidium bromide (AO/EB), Hematoxylin-Eosin (H&E) and DAPI staining assays and flow cytometry analyses indicated that BY4008 has the function of pro-apoptosis and arresting the cell cycle. In addition, BY4008 inhibited the autophosphorylation of EGFR and blocked the activation of downstream signaling and the JAK-STAT3 pathway.

Results: Meanwhile, a decreased level of reactive oxygen species (ROS) and an increased level of malondialdehyde (MDA) in SW620 and HCT116 cells were observed after exposure to BY4008.

Conclusion: In summary, this study provides an important structural basis and mechanistic study for future effective treatment of colorectal cancer.

Keywords: EGFR, JAK3, KRAS mutation, colorectal cancer, dual-target inhibitor, clinical research.

[1]
Siegel, R.; Desantis, C.; Jemal, A. Colorectal cancer statistics, 2014. CA Cancer J. Clin., 2014, 64(2), 104-117.
[http://dx.doi.org/10.3322/caac.21220] [PMID: 24639052]
[2]
Araghi, M.; Soerjomataram, I.; Jenkins, M.; Brierley, J.; Morris, E.; Bray, F.; Arnold, M. Global trends in colorectal cancer mortality: Pro-jections to the year 2035. Int. J. Cancer, 2019, 144(12), 2992-3000.
[http://dx.doi.org/10.1002/ijc.32055] [PMID: 30536395]
[3]
Dekker, E.; Tanis, P.J.; Vleugels, J.L.A.; Kasi, P.M.; Wallace, M.B. Colorectal cancer. Lancet, 2019, 394(10207), 1467-1480.
[http://dx.doi.org/10.1016/S0140-6736(19)32319-0] [PMID: 31631858]
[4]
Sharma, R. An examination of colorectal cancer burden by socioeconomic status: Evidence from GLOBOCAN 2018. EPMA J., 2019, 11(1), 95-117.
[http://dx.doi.org/10.1007/s13167-019-00185-y] [PMID: 32140188]
[5]
Schreuders, E.H.; Ruco, A.; Rabeneck, L.; Schoen, R.E.; Sung, J.J.Y.; Young, G.P.; Kuipers, E.J. Colorectal cancer screening: A global overview of existing programmes. Gut, 2015, 64(10), 1637-1649.
[http://dx.doi.org/10.1136/gutjnl-2014-309086] [PMID: 26041752]
[6]
Keum, N.; Giovannucci, E. Global burden of colorectal cancer: Emerging trends, risk factors and prevention strategies. Nat. Rev. Gastroenterol. Hepatol., 2019, 16(12), 713-732.
[http://dx.doi.org/10.1038/s41575-019-0189-8] [PMID: 31455888]
[7]
Glynne-Jones, R.; Falk, S.; Maughan, T.S.; Meadows, H.M.; Sebag-Montefiore, D. A phase I/II study of irinotecan when added to 5-fluorouracil and leucovorin and pelvic radiation in locally advanced rectal cancer: A colorectal clinical oncology group study. Br. J. Cancer, 2007, 96(4), 551-558.
[http://dx.doi.org/10.1038/sj.bjc.6603570] [PMID: 17262086]
[8]
Ducreux, M.; Bennouna, J.; Hebbar, M.; Ychou, M.; Lledo, G.; Conroy, T.; Adenis, A.; Faroux, R.; Rebischung, C.; Bergougnoux, L.; Kockler, L.; Douillard, J.Y. Capecitabine plus oxaliplatin (XELOX) versus 5-fluorouracil/leucovorin plus oxaliplatin (FOLFOX-6) as first-line treatment for metastatic colorectal cancer. Int. J. Cancer, 2011, 128(3), 682-690.
[http://dx.doi.org/10.1002/ijc.25369] [PMID: 20473862]
[9]
Fornasier, G.; Francescon, S.; Baldo, P. An update of efficacy and safety of cetuximab in metastatic colorectal cancer: A narrative review. Adv. Ther., 2018, 35(10), 1497-1509.
[http://dx.doi.org/10.1007/s12325-018-0791-0] [PMID: 30218345]
[10]
Petrelli, F.; Borgonovo, K.; Cabiddu, M.; Ghilardi, M.; Lonati, V.; Maspero, F.; Sauta, M.G.; Beretta, G.D.; Barni, S. FOLFIRI-bevacizumab as first-line chemotherapy in 3500 patients with advanced colorectal cancer: A pooled analysis of 29 published trials. Clin. Colorectal Cancer, 2013, 12(3), 145-151.
[http://dx.doi.org/10.1016/j.clcc.2013.04.006] [PMID: 23763824]
[11]
Ortega Duran, M.; Shnyder, S.; Sutton, C.; Shaheed, S.U. 535PInvestigation of MSI status in acquired resistance to 5-fluorouracil treat-ment in colorectal cancer using a SILAC-based quantitative proteomic analysis method. Ann. Oncol., 2017, 28(Suppl. 5), v181.
[http://dx.doi.org/10.1093/annonc/mdx393.061]
[12]
Yang, S.Y.; Miah, A.; Sales, K.M.; Fuller, B.; Seifalian, A.M.; Winslet, M. Inhibition of the p38 MAPK pathway sensitises human colon cancer cells to 5-fluorouracil treatment. Int. J. Oncol., 2011, 38(6), 1695-1702.
[http://dx.doi.org/10.3892/ijo.2011.982] [PMID: 21424124]
[13]
Dhillon, S. Regorafenib: A review in metastatic colorectal cancer. Drugs, 2018, 78(11), 1133-1144.
[http://dx.doi.org/10.1007/s40265-018-0938-y] [PMID: 29943375]
[14]
Sun, Q.; Zhou, J.; Zhang, Z.; Guo, M.; Liang, J.; Zhou, F.; Long, J.; Zhang, W.; Yin, F.; Cai, H.; Yang, H.; Zhang, W.; Gu, Y.; Ni, L.; Sai, Y.; Cui, Y.; Zhang, M.; Hong, M.; Sun, J.; Yang, Z.; Qing, W.; Su, W.; Ren, Y. Discovery of fruquintinib, a potent and highly selective small molecule inhibitor of VEGFR 1, 2, 3 tyrosine kinases for cancer therapy. Cancer Biol. Ther., 2014, 15(12), 1635-1645.
[http://dx.doi.org/10.4161/15384047.2014.964087] [PMID: 25482937]
[15]
Rustgi, A.K. BRAF: A driver of the serrated pathway in colon cancer. Cancer Cell, 2013, 24(1), 1-2.
[http://dx.doi.org/10.1016/j.ccr.2013.06.008] [PMID: 23845435]
[16]
Miller, K.D.; Siegel, R.L.; Lin, C.C.; Mariotto, A.B.; Kramer, J.L.; Rowland, J.H.; Stein, K.D.; Alteri, R.; Jemal, A. Cancer treatment and survivorship statistics, 2016. CA Cancer J. Clin., 2016, 66(4), 271-289.
[http://dx.doi.org/10.3322/caac.21349] [PMID: 27253694]
[17]
Ai, M.; Wang, C.; Tang, Z.; Liu, K.; Sun, X.; Ma, T.; Li, Y.; Ma, X.; Li, L.; Chen, L. Design and synthesis of diphenylpyrimidine deriva-tives (DPPYs) as potential dual EGFR T790M and FAK inhibitors against a diverse range of cancer cell lines. Bioorg. Chem., 2020, 94, 103408.
[http://dx.doi.org/10.1016/j.bioorg.2019.103408] [PMID: 31706682]
[18]
Zhu, Y.; Zheng, X.; Wang, C.; Sun, X.; Sun, H.; Ma, T.; Li, Y.; Liu, K.; Chen, L.; Ma, X. Synthesis and biological activity of thieno[3,2-d]pyrimidines as potent JAK3 inhibitors for the treatment of idiopathic pulmonary fibrosis. Bioorg. Med. Chem., 2020, 28(2), 115254.
[http://dx.doi.org/10.1016/j.bmc.2019.115254] [PMID: 31866272]
[19]
Song, Z.; Huang, S.; Yu, H.; Jiang, Y.; Wang, C.; Meng, Q.; Shu, X.; Sun, H.; Liu, K.; Li, Y.; Ma, X. Synthesis and biological evaluation of morpholine-substituted diphenylpyrimidine derivatives (Mor-DPPYs) as potent EGFR T790M inhibitors with improved activity toward the gefitinib-resistant non-small cell lung cancers (NSCLC). Eur. J. Med. Chem., 2017, 133, 329-339.
[http://dx.doi.org/10.1016/j.ejmech.2017.03.083] [PMID: 28395219]
[20]
Liu, H.; Qu, M.; Xu, L.; Han, X.; Wang, C.; Shu, X.; Yao, J.; Liu, K.; Peng, J.; Li, Y.; Ma, X. Design and synthesis of sulfonamide-substituted diphenylpyrimidines (SFA-DPPYs) as potent Bruton’s tyrosine kinase (BTK) inhibitors with improved activity toward B-cell lymphoblastic leukemia. Eur. J. Med. Chem., 2017, 135, 60-69.
[http://dx.doi.org/10.1016/j.ejmech.2017.04.037] [PMID: 28432946]
[21]
Knickelbein, K.; Zhang, L. Mutant KRAS as a critical determinant of the therapeutic response of colorectal cancer. Genes Dis., 2015, 2(1), 4-12.
[http://dx.doi.org/10.1016/j.gendis.2014.10.002] [PMID: 25815366]
[22]
Spano, J.P.; Milano, G.; Rixe, C.; Fagard, R. JAK/STAT signalling pathway in colorectal cancer: A new biological target with therapeutic implications. Eur. J. Cancer, 2006, 42(16), 2668-2670.
[http://dx.doi.org/10.1016/j.ejca.2006.07.006] [PMID: 16963263]
[23]
Srinivas, U.S.; Tan, B.W.Q.; Vellayappan, B.A.; Jeyasekharan, A.D. ROS and the DNA damage response in cancer. Redox Biol., 2019, 25, 101084.
[http://dx.doi.org/10.1016/j.redox.2018.101084] [PMID: 30612957]
[24]
Zhou, M.; Liu, X.; Li, Z.; Huang, Q.; Li, F.; Li, C.Y. Caspase-3 regulates the migration, invasion and metastasis of colon cancer cells. Int. J. Cancer, 2018, 143(4), 921-930.
[http://dx.doi.org/10.1002/ijc.31374] [PMID: 29524226]
[25]
Peña-Blanco, A.; García-Sáez, A.J. Bax, Bak and beyond - mitochondrial performance in apoptosis. FEBS J., 2018, 285(3), 416-431.
[http://dx.doi.org/10.1111/febs.14186] [PMID: 28755482]

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