Login Register Cart 0
Generic placeholder image

Combinatorial Chemistry & High Throughput Screening

Editor-in-Chief

ISSN (Print): 1386-2073
ISSN (Online): 1875-5402

Back
Journal Home About Journal Editorial Board Journal Insight Current Issue Volumes/Issues
Subscribe
Research Article

Investigating the Impact of Different Acrylamide (Electrophilic Warhead) on Osimertinib’s Pharmacological Spectrum by Molecular Mechanic and Quantum Mechanic Approach

Author(s): Harun Patel*, Iqrar Ahmad*, Harsha Jadhav, Rahul Pawara, Deepak Lokwani and Sanjay Surana

Volume 25, Issue 1, 2022

Published on: 04 December, 2020

Page: [149 - 166] Pages: 18

DOI: 10.2174/1386207323666201204125524

Price: $65

Abstract

Background: Lung cancer has become the prominent cause of the cancer-related deaths globally. More than 80 % of all lung cancers have been diagnosed with Non- Small Cell Lung Cancer (NSCLC). The USFDA approved osimertinib to treat patients with metastatic T790M EGFR NSCLC on a regular basis in March 2017. Recently, C797S mutation to osimertinib has been reported, which indicates the need for structural modification to overcome the problem of mutation.

Methods: In this bioinformatics study, we have evaluated the impact of various acrylamide as an electrophilic warhead on the activity and selectivity of osimertinib.

Result: Osimertinib analouge 48, 50, 60, 61, 67, 75, 80, 86, 89, 92, 93, 116 and 124 were the most active and selective compounds against T790M EGFR mutants compared to Osimertinib.

Conclusion: These compounds also showed less inclination towards WT-EGFR.

Keywords: NSCLC, EGFR-T790M, osimertinib, acrylamide, lung cancer, cystein.

« Previous Next »
Graphical Abstract

[1]
Mok, T.S.; Wu, Y.L.; Thongprasert, S.; Yang, C.H.; Chu, D.T.; Saijo, N.; Nishiwaki, Y. Gefitinib or carboplatin–paclitaxel in pulmonary adenocarcinoma. N. Engl. J. Med., 2009, 361, 947-957.
[http://dx.doi.org/10.1056/NEJMoa0810699]
[2]
Mitsudomi, T.; Morita, S.; Yatabe, Y.; Negoro, S.; Okamoto, I.; Tsurutani, J.; Seto, T.; Satouchi, M.; Tada, H.; Hirashima, T.; Asami, K.; Katakami, N.; Takada, M.; Yoshioka, H.; Shibata, K.; Kudoh, S.; Shimizu, E.; Saito, H.; Toyooka, S.; Nakagawa, K.; Fukuoka, M. West Japan Oncology Group. Gefitinib versus cisplatin plus docetaxel in patients with non-small-cell lung cancer harbouring mutations of the epidermal growth factor receptor (WJTOG3405): an open label, randomised phase 3 trial. Lancet Oncol., 2010, 11(2), 121-128.
[http://dx.doi.org/10.1016/S1470-2045(09)70364-X] [PMID: 20022809]
[3]
Maemondo, M.; Inoue, A.; Kobayashi, K.; Sugawara, S.; Oizumi, S.; Isobe, H.; Gemma, A.; Harada, M.; Yoshizawa, H.; Kinoshita, I.; Fujita, Y.; Okinaga, S.; Hirano, H.; Yoshimori, K.; Harada, T.; Ogura, T.; Ando, M.; Miyazawa, H.; Tanaka, T.; Saijo, Y.; Hagiwara, K.; Morita, S.; Nukiwa, T. North-East Japan Study Group. Gefitinib or chemotherapy for non-small-cell lung cancer with mutated EGFR. N. Engl. J. Med., 2010, 362(25), 2380-2388.
[http://dx.doi.org/10.1056/NEJMoa0909530] [PMID: 20573926]
[4]
Rosell, R.; Carcereny, E.; Gervais, R.; Vergnenegre, A.; Massuti, B.; Felip, E.; Porta, R. Erlotinib versus standard chemotherapy as first-line treatment for European patients with advanced EGFR mutation-positive non-small-cell lung cancer (EURTAC): a multicentre, open-label, randomised phase 3 trial. Lancet Oncol., 2012, 13, 239-246.
[5]
Sequist, L.V.J.; Yang, J.C.; Yamamoto, N.; O’Byrne, K.; Hirsh, V.; Mok, T.; Geater, S.L.; Orlov, S.; Tsai, C.M.; Boyer, M.; Su, W.C.; Bennouna, J.; Kato, T.; Gorbunova, V.; Lee, K.H.; Shah, R.; Massey, D.; Zazulina, V.; Shahidi, M.; Schuler, M. Phase III study of afatinib or cisplatin plus pemetrexed in patients with metastatic lung adenocarcinoma with EGFR mutations. J. Clin. Oncol., 2013, 31(27), 3327-3334.
[http://dx.doi.org/10.1200/JCO.2012.44.2806] [PMID: 23816960]
[6]
Ohashi, K.; Sequist, L.V.; Arcila, M.E.; Lovly, C.M.; Chen, X.; Rudin, C.M.; Moran, T.; Camidge, D.R.; Vnencak-Jones, C.L.; Berry, L.; Pan, Y.; Sasaki, H.; Engelman, J.A.; Garon, E.B.; Dubinett, S.M.; Franklin, W.A.; Riely, G.J.; Sos, M.L.; Kris, M.G.; Dias-Santagata, D.; Ladanyi, M.; Bunn, P.A., Jr; Pao, W. Characteristics of lung cancers harboring NRAS mutations. Clin. Cancer Res., 2013, 19(9), 2584-2591.
[http://dx.doi.org/10.1158/1078-0432.CCR-12-3173] [PMID: 23515407]
[7]
Kobayashi, S.; Boggon, T.J.; Dayaram, T.; Jänne, P.A.; Kocher, O.; Meyerson, M.; Johnson, B.E.; Eck, M.J.; Tenen, D.G.; Halmos, B. EGFR mutation and resistance of non-small-cell lung cancer to gefitinib. N. Engl. J. Med., 2005, 352(8), 786-792.
[http://dx.doi.org/10.1056/NEJMoa044238] [PMID: 15728811]
[8]
Pao, W.; Miller, V.A.; Politi, K.A.; Riely, G.J.; Somwar, R.; Zakowski, M.F.; Kris, M.G.; Varmus, H. Acquired resistance of lung adenocarcinomas to gefitinib or erlotinib is associated with a second mutation in the EGFR kinase domain. PLoS Med., 2005, 2(3), e73.
[http://dx.doi.org/10.1371/journal.pmed.0020073] [PMID: 15737014]
[9]
Niederst, M.J.; Engelman, J.A. Bypass mechanisms of resistance to receptor tyrosine kinase inhibition in lung cancer. Sci. Signal., 2013, 6(294), re6-re6.
[http://dx.doi.org/10.1126/scisignal.2004652] [PMID: 24065147]
[10]
Chuang, J.C.; Salahudeen, A.A.; Wakelee, H.A. Rociletinib, a third generation EGFR tyrosine kinase inhibitor: Current data and future directions. Expert Opin. Pharmacother., 2016, 17(7), 989-993.
[http://dx.doi.org/10.1517/14656566.2016.1162786] [PMID: 26950414]
[11]
Walter, A.O.; Sjin, R.T.T.; Haringsma, H.J.; Ohashi, K.; Sun, J.; Lee, K.; Dubrovskiy, A.; Labenski, M.; Zhu, Z.; Wang, Z.; Sheets, M.; St Martin, T.; Karp, R.; van Kalken, D.; Chaturvedi, P.; Niu, D.; Nacht, M.; Petter, R.C.; Westlin, W.; Lin, K.; Jaw-Tsai, S.; Raponi, M.; Van Dyke, T.; Etter, J.; Weaver, Z.; Pao, W.; Singh, J.; Simmons, A.D.; Harding, T.C.; Allen, A. Discovery of a mutant-selective covalent inhibitor of EGFR that overcomes T790M-mediated resistance in NSCLC. Cancer Discov., 2013, 3(12), 1404-1415.
[http://dx.doi.org/10.1158/2159-8290.CD-13-0314] [PMID: 24065731]
[12]
Cross, D.A.; Ashton, S.E.; Ghiorghiu, S.; Eberlein, C.; Nebhan, C.A.; Spitzler, P.J.; Orme, J.P.; Finlay, M.R.; Ward, R.A.; Mellor, M.J.; Hughes, G.; Rahi, A.; Jacobs, V.N.; Red Brewer, M.; Ichihara, E.; Sun, J.; Jin, H.; Ballard, P.; Al-Kadhimi, K.; Rowlinson, R.; Klinowska, T.; Richmond, G.H.; Cantarini, M.; Kim, D.W.; Ranson, M.R.; Pao, W. AZD9291, an irreversible EGFR TKI, overcomes T790M-mediated resistance to EGFR inhibitors in lung cancer. Cancer Discov., 2014, 4(9), 1046-1061.
[http://dx.doi.org/10.1158/2159-8290.CD-14-0337] [PMID: 24893891]
[13]
Zhou, W.; Ercan, D.; Chen, L.; Yun, C.H.; Li, D.; Capelletti, M.; Cortot, A.B.; Chirieac, L.; Iacob, R.E.; Padera, R.; Engen, J.R.; Wong, K.K.; Eck, M.J.; Gray, N.S.; Jänne, P.A. Novel mutant-selective EGFR kinase inhibitors against EGFR T790M. Nature, 2009, 462(7276), 1070-1074.
[http://dx.doi.org/10.1038/nature08622] [PMID: 20033049]
[14]
Hedley, P.L.; Jørgensen, P.; Schlamowitz, S.; Wangari, R.; Moolman-Smook, J.; Brink, P.A.; Kanters, J.K.; Corfield, V.A.; Christiansen, M. The genetic basis of long QT and short QT syndromes: a mutation update. Hum. Mutat., 2009, 30(11), 1486-1511.
[http://dx.doi.org/10.1002/humu.21106] [PMID: 19862833]
[15]
Qin, M.; Wang, T.; Xu, B.; Ma, Z.; Jiang, N.; Xie, H.; Gong, P.; Zhao, Y. Novel hydrazone moiety-bearing aminopyrimidines as selective inhibitors of epidermal growth factor receptor T790M mutant. Eur. J. Med. Chem., 2015, 104, 115-126.
[http://dx.doi.org/10.1016/j.ejmech.2015.09.031] [PMID: 26451770]
[16]
Woyach, J.A.; Furman, R.R.; Liu, T.M.; Ozer, H.G.; Zapatka, M.; Ruppert, A.S.; Xue, L.; Li, D.H.; Steggerda, S.M.; Versele, M.; Dave, S.S.; Zhang, J.; Yilmaz, A.S.; Jaglowski, S.M.; Blum, K.A.; Lozanski, A.; Lozanski, G.; James, D.F.; Barrientos, J.C.; Lichter, P.; Stilgenbauer, S.; Buggy, J.J.; Chang, B.Y.; Johnson, A.J.; Byrd, J.C. Resistance mechanisms for the Bruton’s tyrosine kinase inhibitor ibrutinib. N. Engl. J. Med., 2014, 370(24), 2286-2294.
[http://dx.doi.org/10.1056/NEJMoa1400029] [PMID: 24869598]
[17]
Cheng, S.; Guo, A.; Lu, P.; Ma, J.; Coleman, M.; Wang, Y.L. Functional characterization of BTK(C481S) mutation that confers ibrutinib resistance: exploration of alternative kinase inhibitors. Leukemia, 2015, 29(4), 895-900.
[http://dx.doi.org/10.1038/leu.2014.263] [PMID: 25189416]
[18]
Ferreira, L.G.; Dos Santos, R.N.; Oliva, G.; Andricopulo, A.D. Molecular docking and structure-based drug design strategies. Molecules, 2015, 20(7), 13384-13421.
[http://dx.doi.org/10.3390/molecules200713384] [PMID: 26205061]
[19]
Rehan, M. An anti-cancer drug candidate OSI-027 and its analog as inhibitors of mTOR: computational insights into the inhibitory mechanisms. J. Cell. Biochem., 2017, 118(12), 4558-4567.
[http://dx.doi.org/10.1002/jcb.26117] [PMID: 28475291]
[20]
Rehan, M.; Beg, M.A.; Parveen, S.; Damanhouri, G.A.; Zaher, G.F. Computational insights into the inhibitory mechanism of human AKT1 by an orally active inhibitor, MK-2206. PLoS One, 2014, 9(10), e109705.
[http://dx.doi.org/10.1371/journal.pone.0109705] [PMID: 25329478]
[21]
Jamal, M.S.; Parveen, S.; Beg, M.A.; Suhail, M.; Chaudhary, A.G.; Damanhouri, G.A.; Abuzenadah, A.M.; Rehan, M. Anticancer compound plumbagin and its molecular targets: A structural insight into the inhibitory mechanisms using computational approaches. PLoS One, 2014, 9(2), e87309.
[http://dx.doi.org/10.1371/journal.pone.0087309] [PMID: 24586269]
[22]
Halgren, T.A.; Murphy, R.B.; Friesner, R.A.; Beard, H.S.; Frye, L.L.; Pollard, W.T.; Banks, J.L. Glide: a new approach for rapid, accurate docking and scoring. 2. Enrichment factors in database screening. J. Med. Chem., 2004, 47(7), 1750-1759.
[http://dx.doi.org/10.1021/jm030644s] [PMID: 15027866]
[23]
Evans, D.A.; Doman, T.N.; Thorner, D.A.; Bodkin, M.J. 3D QSAR methods: phase and catalyst compared. J. Chem. Inf. Model., 2007, 47(3), 1248-1257.
[http://dx.doi.org/10.1021/ci7000082] [PMID: 17477520]
[24]
Zhong, H.; Tran, L.M.; Stang, J.L. Induced-fit docking studies of the active and inactive states of protein tyrosine kinases. J. Mol. Graph. Model., 2009, 28(4), 336-346.
[http://dx.doi.org/10.1016/j.jmgm.2009.08.012] [PMID: 19767223]
[25]
Zhu, K.; Borrelli, K.W.; Greenwood, J.R.; Day, T.; Abel, R.; Farid, R.S.; Harder, E. Docking covalent inhibitors: a parameter free approach to pose prediction and scoring. J. Chem. Inf. Model., 2014, 54(7), 1932-1940.
[http://dx.doi.org/10.1021/ci500118s] [PMID: 24916536]
[26]
Vistoli, G.; Pedretti, A.; Testa, B. Assessing drug-likeness--what are we missing? Drug Discov. Today, 2008, 13(7-8), 285-294.
[http://dx.doi.org/10.1016/j.drudis.2007.11.007] [PMID: 18405840]
[27]
Lipinski, C.A.; Lombardo, F.; Dominy, B.W.; Feeney, P.J. Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. Adv. Drug Deliv. Rev., 2001, 46(1-3), 3-26.
[http://dx.doi.org/10.1016/S0169-409X(00)00129-0] [PMID: 11259830]
[28]
Ertl, P.; Rohde, B.; Selzer, P. Fast calculation of molecular polar surface area as a sum of fragment-based contributions and its application to the prediction of drug transport properties. J. Med. Chem., 2000, 43(20), 3714-3717.
[http://dx.doi.org/10.1021/jm000942e] [PMID: 11020286]
[29]
Poroikov, V.V.; Filimonov, D.A.; Gloriozova, T.A.; Lagunin, A.A. Druzhi- lovsky, D. S.; Stepanchikova, A. V. Computer aided prediction of biological activity spectra for substances: Virtual chemogenomics. Herald of Vavilov Society for Geneticists and Breeding Scientists, 2009, 13, 137-143.
[30]
Poroikov, V.; Filimonov, D.; Lagunin, A.; Gloriozova, T.; Zakharov, A. PASS: identification of probable targets and mechanisms of toxicity. SAR QSAR Environ. Res., 2007, 18(1-2), 101-110.
[http://dx.doi.org/10.1080/10629360601054032] [PMID: 17365962]
[31]
Becke, A.D. Density-functional exchange-energy approximation with correct asymptotic behavior. Phys. Rev. A Gen. Phys., 1988, 38(6), 3098-3100.
[http://dx.doi.org/10.1103/PhysRevA.38.3098] [PMID: 9900728]
[32]
Lee, C.; Yang, W.; Parr, R.G. Development of the Colle-Salvetti correlation-energy formula into a functional of the electron density. Phys. Rev. B Condens. Matter, 1988, 37(2), 785-789.
[http://dx.doi.org/10.1103/PhysRevB.37.785] [PMID: 9944570]
[33]
Bochevarov, A.D.; Harder, E.; Hughes, T.F.; Greenwood, J.R.; Braden, D.A.; Philipp, D.M.; Rinaldo, D.; Halls, M.D.; Zhang, J.; Friesner, R.A. Jaguar: A high‐performance quantum chemistry software program with strengths in life and materials sciences. Int. J. Quantum Chem., 2013, 113, 2110-2142.
[http://dx.doi.org/10.1002/qua.24481]
[34]
Patel, H.M.; Ahmad, I.; Pawara, R.; Shaikh, M.; Surana, S. In silico search of triple mutant T790M/C797S allosteric inhibitors to conquer acquired resistance problem in non-small cell lung cancer (NSCLC): a combined approach of structure-based virtual screening and molecular dynamics simulation. J. Biomol. Struct. Dyn., 2020, 1-15.
[http://dx.doi.org/10.1080/07391102.2020.1734092] [PMID: 32102624]
[35]
Patel, H.M.; Shaikh, M.; Ahmad, I.; Lokwani, D.; Surana, S.J. BREED based de novo hybridization approach: generating novel T790M/C797S-EGFR tyrosine kinase inhibitors to overcome the problem of mutation and resistance in non small cell lung cancer (NSCLC). J. Biomol. Struct. Dyn., 2021, 39(8), 2838-2856.
[36]
Patel, H.; Ansari, A.; Pawara, R.; Ansari, I.; Jadhav, H.; Surana, S. Design and synthesis of novel 2,4-disubstituted aminopyrimidines: reversible non-covalent T790M EGFR inhibitors. J. Recept. Signal Transduct. Res., 2018, 38(5-6), 393-412.
[http://dx.doi.org/10.1080/10799893.2018.1557207] [PMID: 31038025]
[37]
Yun, C.H.; Boggon, T.J.; Li, Y.; Woo, M.S.; Greulich, H.; Meyerson, M.; Eck, M.J. Structures of lung cancer-derived EGFR mutants and inhibitor complexes: mechanism of activation and insights into differential inhibitor sensitivity. Cancer Cell, 2007, 11(3), 217-227.
[http://dx.doi.org/10.1016/j.ccr.2006.12.017] [PMID: 17349580]
[38]
Yun, C.H.; Mengwasser, K.E.; Toms, A.V.; Woo, M.S.; Greulich, H.; Wong, K.K.; Meyerson, M.; Eck, M.J. The T790M mutation in EGFR kinase causes drug resistance by increasing the affinity for ATP. Proc. Natl. Acad. Sci. USA, 2008, 105(6), 2070-2075.
[http://dx.doi.org/10.1073/pnas.0709662105] [PMID: 18227510]
[39]
Zhang, X.; Gureasko, J.; Shen, K.; Cole, P.A.; Kuriyan, J. An allosteric mechanism for activation of the kinase domain of epidermal growth factor receptor. Cell, 2006, 125, 1137-1149.
[http://dx.doi.org/10.1016/j.cell.2006.05.013]
[40]
Jackman, D.M.; Miller, V.A.; Cioffredi, L.A.; Yeap, B.Y.; Jänne, P.A.; Riely, G.J.; Ruiz, M.G.; Giaccone, G.; Sequist, L.V.; Johnson, B.E. Impact of epidermal growth factor receptor and KRAS mutations on clinical outcomes in previously untreated non-small cell lung cancer patients: results of an online tumor registry of clinical trials. Clin. Cancer Res., 2009, 15(16), 5267-5273.
[http://dx.doi.org/10.1158/1078-0432.CCR-09-0888] [PMID: 19671843]
[41]
Carey, K.D.; Garton, A.J.; Romero, M.S.; Kahler, J.; Thomson, S.; Ross, S.; Park, F.; Haley, J.D.; Gibson, N.; Sliwkowski, M.X. Kinetic analysis of epidermal growth factor receptor somatic mutant proteins shows increased sensitivity to the epidermal growth factor receptor tyrosine kinase inhibitor, erlotinib. Cancer Res., 2006, 66(16), 8163-8171.
[http://dx.doi.org/10.1158/0008-5472.CAN-06-0453] [PMID: 16912195]
[42]
Zhao, Y.H.; Le, J.; Abraham, M.H.; Hersey, A.; Eddershaw, P.J.; Luscombe, C.N.; Butina, D.; Beck, G.; Sherborne, B.; Cooper, I.; Platts, J.A. Evaluation of human intestinal absorption data and subsequent derivation of a quantitative structure-activity relationship (QSAR) with the Abraham descriptors. J. Pharm. Sci., 2001, 90(6), 749-784.
[http://dx.doi.org/10.1002/jps.1031] [PMID: 11357178]

Rights & Permissions Print Cite
Article Metrics
55
4
1
1
Wayfinder Image
© 2024 Bentham Science Publishers | Privacy Policy