Influence of Amino Acid Mutations and Small Molecules on Targeted Inhibition of Proteins Involved in Cancer

Author(s): V. Kanakaveti, P. Anoosha, R. Sakthivel, S.K. Rayala, M.M. Gromiha*.

Journal Name: Current Topics in Medicinal Chemistry

Volume 19 , Issue 6 , 2019

Become EABM
Become Reviewer

Graphical Abstract:


Abstract:

Background: Protein-protein interactions (PPIs) are of crucial importance in regulating the biological processes of cells both in normal and diseased conditions. Significant progress has been made in targeting PPIs using small molecules and achieved promising results. However, PPI drug discovery should be further accelerated with better understanding of chemical space along with various functional aspects.

Objective: In this review, we focus on the advancements in computational research for targeted inhibition of protein-protein interactions involved in cancer.

Methods: Here, we mainly focused on two aspects: (i) understanding the key roles of amino acid mutations in epidermal growth factor receptor (EGFR) as well as mutation-specific inhibitors and (ii) design of small molecule inhibitors for Bcl-2 to disrupt PPIs.

Results: The paradigm of PPI inhibition to date reflect the certainty that inclination towards novel and versatile strategies enormously dictate the success of PPI inhibition. As the chemical space highly differs from the normal drug like compounds the lead optimization process has to be given the utmost priority to ensure the clinical success. Here, we provided a broader perspective on effect of mutations in oncogene EGFR connected to Bcl-2 PPIs and focused on the potential challenges.

Conclusion: Understanding and bridging mutations and altered PPIs will provide insights into the alarming signals leading to massive malfunctioning of a biological system in various diseases. Finding rational elucidations from a pharmaceutical stand point will presumably broaden the horizons in future.

Keywords: EGFR, Bcl-2, Protein-protein interactions, Drug targets, Mutation, Cancer.

[1]
Hanahan, D.; Weinberg, R.A. Hallmarks of cancer: The next generation. Cell, 2011, 144(5), 646-674.
[http://dx.doi.org/10.1016/j.cell.2011.02.013] [PMID: 21376230]
[2]
Chen, L.; Willis, S.N.; Wei, A.; Smith, B.J.; Fletcher, J.I.; Hinds, M.G.; Colman, P.M.; Day, C.L.; Adams, J.M.; Huang, D.C. Differential targeting of prosurvival Bcl-2 proteins by their BH3-only ligands allows complementary apoptotic function. Mol. Cell, 2005, 17(3), 393-403.
[http://dx.doi.org/10.1016/j.molcel.2004.12.030] [PMID: 15694340]
[3]
Zhang, Q.C.; Petrey, D.; Deng, L.; Qiang, L.; Shi, Y.; Thu, C.A.; Bisikirska, B.; Lefebvre, C.; Accili, D.; Hunter, T.; Maniatis, T.; Califano, A.; Honig, B. Structure-based prediction of protein-protein interactions on a genome-wide scale. Nature, 2012, 490(7421), 556-560.
[http://dx.doi.org/10.1038/nature11503] [PMID: 23023127]
[4]
Jones, S.; Thornton, J.M. Principles of protein-protein interactions. Proc. Natl. Acad. Sci. USA, 1996, 93(1), 13-20.
[http://dx.doi.org/10.1073/pnas.93.1.13] [PMID: 8552589]
[5]
Jemimah, S.; Yugandhar, K.; Michael Gromiha, M. PROXiMATE: A database of mutant protein-protein complex thermodynamics and kinetics. Bioinformatics, 2017, 33(17), 2787-2788.
[http://dx.doi.org/10.1093/bioinformatics/btx312] [PMID: 28498885]
[6]
Gromiha, M.M.; Yugandhar, K.; Jemimah, S. Protein-protein interactions: Scoring schemes and binding affinity. Curr. Opin. Struct. Biol., 2017, 44, 31-38.
[http://dx.doi.org/10.1016/j.sbi.2016.10.016] [PMID: 27866112]
[7]
Miller, S. The structure of interfaces between subunits of dimeric and tetrameric proteins. Protein Eng., 1989, 3(2), 77-83.
[http://dx.doi.org/10.1093/protein/3.2.77] [PMID: 2594726]
[8]
Larsen, T.A.; Olson, A.J.; Goodsell, D.S. Morphology of protein-protein interfaces. Structure, 1998, 6(4), 421-427.
[http://dx.doi.org/10.1016/S0969-2126(98)00044-6] [PMID: 9562553]
[9]
Keskin, O.; Gursoy, A.; Ma, B.; Nussinov, R. Principles of protein-protein interactions: What are the preferred ways for proteins to interact? Chem. Rev., 2008, 108(4), 1225-1244.
[http://dx.doi.org/ 10.1021/cr040409x] [PMID: 18355092]
[10]
Moreira, I.S.; Fernandes, P.A.; Ramos, M.J. Hot spots-A review of the protein-protein interface determinant amino-acid residues. Proteins, 2007, 68(4), 803-812.
[http://dx.doi.org/10.1002/prot.21396] [PMID: 17546660]
[11]
Pérot, S.; Sperandio, O.; Miteva, M.A.; Camproux, A.C.; Villoutreix, B.O. Druggable pockets and binding site centric chemical space: a paradigm shift in drug discovery. Drug Discov. Today, 2010, 15(15-16), 656-667.
[http://dx.doi.org/10.1016/j.drudis.2010.05.015] [PMID: 20685398]
[12]
Gao, M.; Skolnick, J. The distribution of ligand-binding pockets around protein-protein interfaces suggests a general mechanism for pocket formation. Proc. Natl. Acad. Sci. USA, 2012, 109(10), 3784-3789.
[http://dx.doi.org/10.1073/pnas.1117768109] [PMID: 22355140]
[13]
Scott, D.E.; Bayly, A.R.; Abell, C.; Skidmore, J. Small molecules, big targets: Drug discovery faces the protein-protein interaction challenge. Nat. Rev. Drug Discov., 2016, 15(8), 533-550.
[http://dx.doi.org/10.1038/nrd.2016.29] [PMID: 27050677]
[14]
Nero, T.L.; Morton, C.J.; Holien, J.K.; Wielens, J.; Parker, M.W. Oncogenic protein interfaces: small molecules, big challenges. Nat. Rev. Cancer, 2014, 14(4), 248-262.
[http://dx.doi.org/ 10.1038/nrc3690] [PMID: 24622521]
[15]
Arkin, M.R.; Wells, J.A. Small-molecule inhibitors of protein-protein interactions: Progressing towards the dream. Nat. Rev. Drug Discov., 2004, 3(4), 301-317.
[http://dx.doi.org/ 10.1038/nrd1343] [PMID: 15060526]
[16]
Watanabe, N.; Osada, H. Phosphorylation-dependent protein-protein interaction modules as potential molecular targets for cancer therapy. Curr. Drug Targets, 2012, 13(13), 1654-1658.
[http://dx.doi.org/10.2174/138945012803530035] [PMID: 23030498]
[17]
Müller, S.; Brown, P.J. Epigenetic chemical probes. Clin. Pharmacol. Ther., 2012, 92(6), 689-693.
[http://dx.doi.org/10.1038/clpt.2012.154] [PMID: 23093316]
[18]
Fu, H.; Subramanian, R.R.; Masters, S.C. 14-3-3 proteins: Structure, function, and regulation. Annu. Rev. Pharmacol. Toxicol., 2000, 40, 617-647.
[http://dx.doi.org/10.1146/annurev.pharmtox.40.1.617] [PMID: 10836149]
[19]
Mason, J.M. Design and development of peptides and peptide mimetics as antagonists for therapeutic intervention. Future Med. Chem., 2010, 2(12), 1813-1822.
[http://dx.doi.org/10.4155/fmc.10.259] [PMID: 21428804]
[20]
Billard, C. Design of novel BH3 mimetics for the treatment of chronic lymphocytic leukemia. Leukemia, 2012, 26(9), 2032-2038.
[http://dx.doi.org/10.1038/leu.2012.88] [PMID: 22453662]
[21]
Flygare, J.A.; Beresini, M.; Budha, N.; Chan, H.; Chan, I.T.; Cheeti, S.; Cohen, F.; Deshayes, K.; Doerner, K.; Eckhardt, S.G.; Elliott, L.O.; Feng, B.; Franklin, M.C.; Reisner, S.F.; Gazzard, L.; Halladay, J.; Hymowitz, S.G.; La, H.; LoRusso, P.; Maurer, B.; Murray, L.; Plise, E.; Quan, C.; Stephan, J.P.; Young, S.G.; Tom, J.; Tsui, V.; Um, J.; Varfolomeev, E.; Vucic, D.; Wagner, A.J.; Wallweber, H.J.; Wang, L.; Ware, J.; Wen, Z.; Wong, H.; Wong, J.M.; Wong, M.; Wong, S.; Yu, R.; Zobel, K.; Fairbrother, W.J. Discovery of a potent small-molecule antagonist of inhibitor of apoptosis (IAP) proteins and clinical candidate for the treatment of cancer (GDC-0152). J. Med. Chem., 2012, 55(9), 4101-4113.
[http://dx.doi.org/10.1021/jm300060k] [PMID: 22413863]
[22]
Houghton, P.J.; Kang, M.H.; Reynolds, C.P.; Morton, C.L.; Kolb, E.A.; Gorlick, R.; Keir, S.T.; Carol, H.; Lock, R.; Maris, J.M.; Billups, C.A.; Smith, M.A. Initial testing (stage 1) of LCL161, A SMAC mimetic, by the pediatric preclinical testing program. Pediatr. Blood Cancer, 2012, 58(4), 636-639.
[http://dx.doi.org/10.1002/pbc.23167] [PMID: 21681929]
[23]
Rew, Y.; Sun, D.; Gonzalez-Lopez De Turiso, F.; Bartberger, M.D.; Beck, H.P.; Canon, J.; Chen, A.; Chow, D.; Deignan, J.; Fox, B.M.; Gustin, D.; Huang, X.; Jiang, M.; Jiao, X.; Jin, L.; Kayser, F.; Kopecky, D.J.; Li, Y.; Lo, M.C.; Long, A.M.; Michelsen, K.; Oliner, J.D.; Osgood, T.; Ragains, M.; Saiki, A.Y.; Schneider, S.; Toteva, M.; Yakowec, P.; Yan, X.; Ye, Q.; Yu, D.; Zhao, X.; Zhou, J.; Medina, J.C.; Olson, S.H. Structure-based design of novel inhibitors of the MDM2-p53 interaction. J. Med. Chem., 2012, 55(11), 4936-4954.
[http://dx.doi.org/10.1021/jm300354j] [PMID: 22524527]
[24]
Moellering, R.E.; Cornejo, M.; Davis, T.N.; Del Bianco, C.; Aster, J.C.; Blacklow, S.C.; Kung, A.L.; Gilliland, D.G.; Verdine, G.L.; Bradner, J.E. Direct inhibition of the NOTCH transcription factor complex. Nature, 2009, 462(7270), 182-188.
[http://dx.doi.org/ 10.1038/nature08543] [PMID: 19907488]
[25]
Rubinstein, M.; Niv, M.Y. Peptidic modulators of protein-protein interactions: Progress and challenges in computational design. Biopolymers, 2009, 91(7), 505-513.
[http://dx.doi.org/ 10.1002/bip.21164] [PMID: 19226619]
[26]
Rothe, A.; Hosse, R.J.; Power, B.E. In vitro display technologies reveal novel biopharmaceutics. FASEB J., 2006, 20(10), 1599-1610.
[http://dx.doi.org/10.1096/fj.05-5650rev] [PMID: 16873883]
[27]
Cummings, C.G.; Hamilton, A.D. Disrupting protein-protein interactions with non-peptidic, small molecule alpha-helix mimetics. Curr. Opin. Chem. Biol., 2010, 14(3), 341-346.
[http://dx.doi.org/ 10.1016/j.cbpa.2010.04.001] [PMID: 20430687]
[28]
Whitby, L.R.; Boger, D.L. Comprehensive peptidomimetic libraries targeting protein-protein interactions. Acc. Chem. Res., 2012, 45(10), 1698-1709.
[http://dx.doi.org/10.1021/ar300025n] [PMID: 22799570]
[29]
Brown, C.J.; Quah, S.T.; Jong, J.; Goh, A.M.; Chiam, P.C.; Khoo, K.H.; Choong, M.L.; Lee, M.A.; Yurlova, L.; Zolghadr, K.; Joseph, T.L.; Verma, C.S.; Lane, D.P. Stapled peptides with improved potency and specificity that activate p53. ACS Chem. Biol., 2013, 8(3), 506-512.
[http://dx.doi.org/10.1021/cb3005148] [PMID: 23214419]
[30]
Henchey, L.K.; Jochim, A.L.; Arora, P.S. Contemporary strategies for the stabilization of peptides in the alpha-helical conformation. Curr. Opin. Chem. Biol., 2008, 12(6), 692-697.
[http://dx.doi.org/10.1016/j.cbpa.2008.08.019] [PMID: 18793750]
[31]
Kawamoto, S.A.; Coleska, A.; Ran, X.; Yi, H.; Yang, C.Y.; Wang, S. Design of triazole-stapled BCL9 α-helical peptides to target the β-catenin/B-cell CLL/lymphoma 9 (BCL9) protein-protein interaction. J. Med. Chem., 2012, 55(3), 1137-1146.
[http://dx.doi.org/10.1021/jm201125d] [PMID: 22196480]
[32]
Verdine, G.L.; Walensky, L.D. The challenge of drugging undruggable targets in cancer: lessons learned from targeting BCL-2 family members. Clin. Cancer Res., 2007, 13(24), 7264-7270.
[http://dx.doi.org/10.1158/1078-0432.CCR-07-2184] [PMID: 18094406]
[33]
Blundell, T.L.; Sibanda, B.L.; Montalvão, R.W.; Brewerton, S.; Chelliah, V.; Worth, C.L.; Harmer, N.J.; Davies, O.; Burke, D. Structural biology and bioinformatics in drug design: Opportunities and challenges for target identification and lead discovery. Philos. Trans. R. Soc. Lond. B Biol. Sci., 2006, 361(1467), 413-423.
[http://dx.doi.org/10.1098/rstb.2005.1800] [PMID: 16524830]
[34]
Du, Y.; Nikolovska-Coleska, Z.; Qui, M.; Li, L.; Lewis, I.; Dingledine, R.; Stuckey, J.A.; Krajewski, K.; Roller, P.P.; Wang, S.; Fu, H. A dual-readout F2 assay that combines fluorescence resonance energy transfer and fluorescence polarization for monitoring bimolecular interactions. Assay Drug Dev. Technol., 2011, 9(4), 382-393.
[http://dx.doi.org/10.1089/adt.2010.0292] [PMID: 21395401]
[35]
Navratilova, I.; Hopkins, A.L. Emerging role of surface plasmon resonance in fragment-based drug discovery. Future Med. Chem., 2011, 3(14), 1809-1820.
[http://dx.doi.org/10.4155/fmc.11.128] [PMID: 22004086]
[36]
Skwarczynska, M.; Ottmann, C. Protein-protein interactions as drug targets. Future Med. Chem., 2015, 7(16), 2195-2219.
[http://dx.doi.org/10.4155/fmc.15.138] [PMID: 26510391]
[37]
Vassilev, L.T.; Vu, B.T.; Graves, B.; Carvajal, D.; Podlaski, F.; Filipovic, Z.; Kong, N.; Kammlott, U.; Lukacs, C.; Klein, C.; Fotouhi, N.; Liu, E.A. In vivo activation of the p53 pathway by small-molecule antagonists of MDM2. Science, 2004, 303(5659), 844-848.
[http://dx.doi.org/10.1126/science.1092472] [PMID: 14704432]
[38]
Grasberger, B.L.; Lu, T.; Schubert, C.; Parks, D.J.; Carver, T.E.; Koblish, H.K.; Cummings, M.D.; LaFrance, L.V.; Milkiewicz, K.L.; Calvo, R.R.; Maguire, D.; Lattanze, J.; Franks, C.F.; Zhao, S.; Ramachandren, K.; Bylebyl, G.R.; Zhang, M.; Manthey, C.L.; Petrella, E.C.; Pantoliano, M.W.; Deckman, I.C.; Spurlino, J.C.; Maroney, A.C.; Tomczuk, B.E.; Molloy, C.J.; Bone, R.F. Discovery and cocrystal structure of benzodiazepinedione HDM2 antagonists that activate p53 in cells. J. Med. Chem., 2005, 48(4), 909-912.
[http://dx.doi.org/10.1021/jm049137g] [PMID: 15715460]
[39]
Allen, J.G.; Bourbeau, M.P.; Wohlhieter, G.E.; Bartberger, M.D.; Michelsen, K.; Hungate, R.; Gadwood, R.C.; Gaston, R.D.; Evans, B.; Mann, L.W.; Matison, M.E.; Schneider, S.; Huang, X.; Yu, D.; Andrews, P.S.; Reichelt, A.; Long, A.M.; Yakowec, P.; Yang, E.Y.; Lee, T.A.; Oliner, J.D. Discovery and optimization of chromenotriazolopyrimidines as potent inhibitors of the mouse double minute 2-tumor protein 53 protein-protein interaction. J. Med. Chem., 2009, 52(22), 7044-7053.
[http://dx.doi.org/ 10.1021/jm900681h] [PMID: 19856920]
[40]
Blackburn, T.J.; Ahmed, S.; Coxon, C.R.; Liu, J.; Lu, X.; Golding, B.T.; Griffin, R.J.; Hutton, C.; Newell, D.R.; Ojo, S.; Watson, A.F.; Zaytzev, A.; Zhao, Y.; Lunec, J.; Hardcastle, I.R. Diaryl- and triaryl-pyrrole derivatives: inhibitors of the MDM2-p53 and MDMX-p53 protein-protein interactionsdaggerElectronic supplementary information (ESI) available: Experimental details for compound synthesis, analytical data for all compounds and intermediates. Details for the biological evaluation. Further details for the modeling. MedChemComm, 2013, 4, 1297-1304.
[http://dx.doi.org/ 10.1039/c3md00161j]
[41]
Kenny, C.H.; Ding, W.; Kelleher, K.; Benard, S.; Dushin, E.G.; Sutherland, A.G.; Mosyak, L.; Kriz, R.; Ellestad, G. Development of a fluorescence polarization assay to screen for inhibitors of the FtsZ/ZipA interaction. Anal. Biochem., 2003, 323(2), 224-233.
[http://dx.doi.org/10.1016/j.ab.2003.08.033] [PMID: 14656529]
[42]
White, P.W.; Titolo, S.; Brault, K.; Thauvette, L.; Pelletier, A.; Welchner, E.; Bourgon, L.; Doyon, L.; Ogilvie, W.W.; Yoakim, C.; Cordingley, M.G.; Archambault, J. Inhibition of human papillomavirus DNA replication by small molecule antagonists of the E1-E2 protein interaction. J. Biol. Chem., 2003, 278(29), 26765-26772.
[http://dx.doi.org/10.1074/jbc.M303608200] [PMID: 12730224]
[43]
Wells, J.A.; McClendon, C.L. Reaching for high-hanging fruit in drug discovery at protein-protein interfaces. Nature, 2007, 450(7172), 1001-1009.
[http://dx.doi.org/10.1038/nature06526] [PMID: 18075579]
[44]
Hajduk, P.J.; Greer, J. A decade of fragment-based drug design: Strategic advances and lessons learned. Nat. Rev. Drug Discov., 2007, 6(3), 211-219.
[http://dx.doi.org/10.1038/nrd2220] [PMID: 17290284]
[45]
Whittaker, M. Picking up the pieces with FBDD or FADD: Invest early for future success. Drug Discov. Today, 2009, 14(13-14), 623-624.
[http://dx.doi.org/10.1016/j.drudis.2009.05.011] [PMID: 19486947]
[46]
Blundell, T.L.; Jhoti, H.; Abell, C. High-throughput crystallography for lead discovery in drug design. Nat. Rev. Drug Discov., 2002, 1(1), 45-54.
[http://dx.doi.org/10.1038/nrd706] [PMID: 12119609]
[47]
Scott, D.E.; Ehebauer, M.T.; Pukala, T.; Marsh, M.; Blundell, T.L.; Venkitaraman, A.R.; Abell, C.; Hyvönen, M. Using a fragment-based approach to target protein-protein interactions. ChemBioChem, 2013, 14(3), 332-342.
[http://dx.doi.org/10.1002/cbic.201200521] [PMID: 23344974]
[48]
Lo, M.C.; Aulabaugh, A.; Jin, G.; Cowling, R.; Bard, J.; Malamas, M.; Ellestad, G. Evaluation of fluorescence-based thermal shift assays for hit identification in drug discovery. Anal. Biochem., 2004, 332(1), 153-159.
[http://dx.doi.org/10.1016/j.ab.2004.04.031] [PMID: 15301960]
[49]
Chen, Y.; Inoyama, D.; Kong, A.N.; Beamer, L.J.; Hu, L. Kinetic analyses of Keap1-Nrf2 interaction and determination of the minimal Nrf2 peptide sequence required for Keap1 binding using surface plasmon resonance. Chem. Biol. Drug Des., 2011, 78(6), 1014-1021.
[http://dx.doi.org/10.1111/j.1747-0285.2011.01240.x] [PMID: 21920027]
[50]
Lepre, C.A.; Connolly, P.J.; Moore, J.M. NMR in fragment-based drug discovery; Drug Design, 2010, pp. 41-58.
[http://dx.doi.org/ 10.1017/CBO9780511730412.006]
[51]
Davies, T.G.; Tickle, I.J. Fragment screening using X-ray crystallography. Top. Curr. Chem., 2012, 317, 33-59.
[http://dx.doi.org/ 10.1007/128_2011_179] [PMID: 21678136]
[52]
Lemmon, M.A.; Schlessinger, J. Cell signaling by receptor tyrosine kinases. Cell, 2010, 141(7), 1117-1134.
[http://dx.doi.org/ 10.1016/j.cell.2010.06.011] [PMID: 20602996]
[53]
Petschnigg, J.; Kotlyar, M.; Blair, L.; Jurisica, I.; Stagljar, I.; Ketteler, R. Systematic Identification of Oncogenic EGFR Interaction Partners. J. Mol. Biol., 2017, 429(2), 280-294.
[http://dx.doi.org/ 10.1016/j.jmb.2016.12.006] [PMID: 27956147]
[54]
Kancha, R.K.; von Bubnoff, N.; Peschel, C.; Duyster, J. Functional analysis of epidermal growth factor receptor (EGFR) mutations and potential implications for EGFR targeted therapy. Clin. Cancer Res., 2009, 15(2), 460-467.
[http://dx.doi.org/10.1158/1078-0432.CCR-08-1757] [PMID: 19147750]
[55]
Greulich, H.; Chen, T.H.; Feng, W.; Jänne, P.A.; Alvarez, J.V.; Zappaterra, M.; Bulmer, S.E.; Frank, D.A.; Hahn, W.C.; Sellers, W.R.; Meyerson, M. Oncogenic transformation by inhibitor-sensitive and -resistant EGFR mutants. PLoS Med., 2005, 2(11), e313.
[http://dx.doi.org/10.1371/journal.pmed.0020313] [PMID: 16187797]
[56]
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]
[57]
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]
[58]
Chou, T.Y.; Chiu, C.H.; Li, L.H.; Hsiao, C.Y.; Tzen, C.Y.; Chang, K.T.; Chen, Y.M.; Perng, R.P.; Tsai, S.F.; Tsai, C.M. Mutation in the tyrosine kinase domain of epidermal growth factor receptor is a predictive and prognostic factor for gefitinib treatment in patients with non-small cell lung cancer. Clin. Cancer Res., 2005, 11(10), 3750-3757.
[http://dx.doi.org/10.1158/1078-0432.CCR-04-1981] [PMID: 15897572]
[59]
Nagahara, H.; Mimori, K.; Ohta, M.; Utsunomiya, T.; Inoue, H.; Barnard, G.F.; Ohira, M.; Hirakawa, K.; Mori, M. Somatic mutations of epidermal growth factor receptor in colorectal carcinoma. Clin. Cancer Res., 2005, 11(4), 1368-1371.
[http://dx.doi.org/ 10.1158/1078-0432.CCR-04-1894] [PMID: 15746034]
[60]
Iengar, P. An analysis of substitution, deletion and insertion mutations in cancer genes. Nucleic Acids Res., 2012, 40(14), 6401-6413.
[http://dx.doi.org/10.1093/nar/gks290] [PMID: 22492711]
[61]
Kandoth, C.; McLellan, M.D.; Vandin, F.; Ye, K.; Niu, B.; Lu, C.; Xie, M.; Zhang, Q.; McMichael, J.F.; Wyczalkowski, M.A.; Leiserson, M.D.M.; Miller, C.A.; Welch, J.S.; Walter, M.J.; Wendl, M.C.; Ley, T.J.; Wilson, R.K.; Raphael, B.J.; Ding, L. Mutational landscape and significance across 12 major cancer types. Nature, 2013, 502(7471), 333-339.
[http://dx.doi.org/10.1038/nature12634] [PMID: 24132290]
[62]
Bozic, I.; Antal, T.; Ohtsuki, H.; Carter, H.; Kim, D.; Chen, S.; Karchin, R.; Kinzler, K.W.; Vogelstein, B.; Nowak, M.A. Accumulation of driver and passenger mutations during tumor progression. Proc. Natl. Acad. Sci. USA, 2010, 107(43), 18545-18550.
[http://dx.doi.org/10.1073/pnas.1010978107] [PMID: 20876136]
[63]
Anoosha, P.; Huang, L.T.; Sakthivel, R.; Karunagaran, D.; Gromiha, M.M. Discrimination of driver and passenger mutations in epidermal growth factor receptor in cancer. Mutat. Res., 2015, 780, 24-34.
[http://dx.doi.org/10.1016/j.mrfmmm.2015.07.005] [PMID: 26264175]
[64]
Anoosha, P.; Sakthivel, R.; Michael Gromiha, M. Exploring preferred amino acid mutations in cancer genes: Applications to identify potential drug targets. Biochim. Biophys. Acta, 2016, 1862(2), 155-165.
[http://dx.doi.org/10.1016/j.bbadis.2015.11.006] [PMID: 26581171]
[65]
Gnad, F.; Baucom, A.; Mukhyala, K.; Manning, G.; Zhang, Z. Assessment of computational methods for predicting the effects of missense mutations in human cancers. BMC Genomics, 2013, 14(Suppl. 3), S7.
[PMID: 23819521]
[66]
González-Pérez, A.; López-Bigas, N. Improving the assessment of the outcome of nonsynonymous SNVs with a consensus deleteriousness score, Condel. Am. J. Hum. Genet., 2011, 88(4), 440-449.
[http://dx.doi.org/10.1016/j.ajhg.2011.03.004] [PMID: 21457909]
[67]
Eck, M.J.; Yun, C.H. Structural and mechanistic underpinnings of the differential drug sensitivity of EGFR mutations in non-small cell lung cancer. Biochim. Biophys. Acta, 2010, 1804(3), 559-566.
[http://dx.doi.org/10.1016/j.bbapap.2009.12.010] [PMID: 20026433]
[68]
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]
[69]
Goyal, S.; Jamal, S.; Shanker, A.; Grover, A. Structural investigations of T854A mutation in EGFR and identification of novel inhibitors using structure activity relationships. BMC Genomics, 2015, 16(Suppl. 5), S8.
[http://dx.doi.org/10.1186/1471-2164-16-S5-S8] [PMID: 26041145]
[70]
Yoshikawa, S.; Kukimoto-Niino, M.; Parker, L.; Handa, N.; Terada, T.; Fujimoto, T.; Terazawa, Y.; Wakiyama, M.; Sato, M.; Sano, S.; Kobayashi, T.; Tanaka, T.; Chen, L.; Liu, Z.J.; Wang, B.C.; Shirouzu, M.; Kawa, S.; Semba, K.; Yamamoto, T.; Yokoyama, S. Structural basis for the altered drug sensitivities of non-small cell lung cancer-associated mutants of human epidermal growth factor receptor. Oncogene, 2013, 32(1), 27-38.
[http://dx.doi.org/10.1038/onc.2012.21] [PMID: 22349823]
[71]
Singh, M.; Jadhav, H.R. Targeting non-small cell lung cancer with small-molecule EGFR tyrosine kinase inhibitors. Drug Discov. Today, 2018, 23(3), 745-753.
[http://dx.doi.org/10.1016/j.drudis.2017.10.004] [PMID: 29031620]
[72]
Wang, B.; Shen, W.; Yang, H.; Shen, J.; Sun, T. Targeting EGFR mutants with non-cognate kinase inhibitors in non-small cell lung cancer. Med. Chem. Res., 2014, 23, 4510-4530.
[http://dx.doi.org/ 10.1007/s00044-014-1012-2]
[73]
Anoosha, P.; Sakthivel, R.; Gromiha, M.M. Investigating mutation-specific biological activities of small molecules using quantitative structure-activity relationship for epidermal growth factor receptor in cancer. Mutat. Res., 2017, 806, 19-26.
[http://dx.doi.org/ 10.1016/j.mrfmmm.2017.08.003] [PMID: 28938109]
[74]
Milojkovic, D.; Apperley, J. Mechanisms of resistance to imatinib and second-generation tyrosine inhibitors in chronic myeloid leukemia. Clin. Cancer Res., 2009, 15(24), 7519-7527.
[http://dx.doi.org/10.1158/1078-0432.CCR-09-1068] [PMID: 20008852]
[75]
Bixby, D.; Talpaz, M. Seeking the causes and solutions to imatinib-resistance in chronic myeloid leukemia. Leukemia, 2011, 25(1), 7-22.
[http://dx.doi.org/10.1038/leu.2010.238] [PMID: 21102425]
[76]
Milojkovic, D.; Apperley, J. Mechanisms of resistance to Imatinib and second-generation tyrosine inhibitors in chronic myeloid leukemia. Clin. Cancer Res., 2009, 15(24), 7519-7527.
[http://dx.doi.org/10.1158/1078-0432.CCR-09-1068] [PMID: 20008852]
[77]
Lessene, G.; Czabotar, P.E.; Colman, P.M. BCL-2 family antagonists for cancer therapy. Nat. Rev. Drug Discov., 2008, 7(12), 989-1000.
[http://dx.doi.org/10.1038/nrd2658] [PMID: 19043450]
[78]
Vogler, M.; Dinsdale, D.; Dyer, M.J.; Cohen, G.M. Bcl-2 inhibitors: Small molecules with a big impact on cancer therapy. Cell Death Differ., 2009, 16(3), 360-367.
[http://dx.doi.org/ 10.1038/cdd.2008.137] [PMID: 18806758]
[79]
Petsalaki, E.; Russell, R.B. Peptide-mediated interactions in biological systems: New discoveries and applications. Curr. Opin. Biotechnol., 2008, 19(4), 344-350.
[http://dx.doi.org/10.1016/j.copbio.2008.06.004] [PMID: 18602004]
[80]
Raj, M.; Bullock, B.N.; Arora, P.S. Plucking the high hanging fruit: A systematic approach for targeting protein-protein interactions. Bioorg. Med. Chem., 2013, 21(14), 4051-4057.
[http://dx.doi.org/ 10.1016/j.bmc.2012.11.023] [PMID: 23267671]
[81]
London, N.; Raveh, B.; Schueler-Furman, O. Druggable protein-protein interactions--From hot spots to hot segments. Curr. Opin. Chem. Biol., 2013, 17(6), 952-959.
[http://dx.doi.org/ 10.1016/j.cbpa.2013.10.011] [PMID: 24183815]
[82]
Kanakaveti, V.; Sakthivel, R.; Rayala, S.K.; Gromiha, M.M. Importance of functional groups in predicting the activity of small molecule inhibitors for Bcl-2 and Bcl-xL. Chem. Biol. Drug Des., 2017, 90(2), 308-316.
[http://dx.doi.org/10.1111/cbdd.12952] [PMID: 28112863]
[83]
Sattler, M.; Liang, H.; Nettesheim, D.; Meadows, R.P.; Harlan, J.E.; Eberstadt, M.; Yoon, H.S.; Shuker, S.B.; Chang, B.S.; Minn, A.J.; Thompson, C.B.; Fesik, S.W. Structure of Bcl-xL-Bak peptide complex: recognition between regulators of apoptosis. Science, 1997, 275(5302), 983-986.
[http://dx.doi.org/10.1126/science.275.5302.983] [PMID: 9020082]
[84]
Oltersdorf, T.; Elmore, S.W.; Shoemaker, A.R.; Armstrong, R.C.; Augeri, D.J.; Belli, B.A.; Bruncko, M.; Deckwerth, T.L.; Dinges, J.; Hajduk, P.J.; Joseph, M.K.; Kitada, S.; Korsmeyer, S.J.; Kunzer, A.R.; Letai, A.; Li, C.; Mitten, M.J.; Nettesheim, D.G.; Ng, S.; Nimmer, P.M.; O’Connor, J.M.; Oleksijew, A.; Petros, A.M.; Reed, J.C.; Shen, W.; Tahir, S.K.; Thompson, C.B.; Tomaselli, K.J.; Wang, B.; Wendt, M.D.; Zhang, H.; Fesik, S.W.; Rosenberg, S.H. An inhibitor of Bcl-2 family proteins induces regression of solid tumours. Nature, 2005, 435(7042), 677-681.
[http://dx.doi.org/ 10.1038/nature03579] [PMID: 15902208]
[85]
Arkin, M.R.; Wells, J.A. Small-molecule inhibitors of protein-protein interactions: Progressing towards the dream. Nat. Rev. Drug Discov., 2004, 3(4), 301-317.
[http://dx.doi.org/10.1038/nrd1343] [PMID: 15060526]
[86]
Biros, S.M.; Moisan, L.; Mann, E.; Carella, A.; Zhai, D.; Reed, J.C.; Rebek, J., Jr Heterocyclic alpha-helix mimetics for targeting protein-protein interactions. Bioorg. Med. Chem. Lett., 2007, 17(16), 4641-4645.
[http://dx.doi.org/10.1016/j.bmcl.2007.05.075] [PMID: 17555961]
[87]
Wakui, N.; Yoshino, R.; Yasuo, N.; Ohue, M.; Sekijima, M. Exploring the selectivity of inhibitor complexes with Bcl-2 and Bcl-XL: A molecular dynamics simulation approach. J. Mol. Graph. Model., 2018, 79, 166-174.
[http://dx.doi.org/10.1016/j.jmgm.2017.11.011] [PMID: 29197725]
[88]
Pelay-Gimeno, M.; Glas, A.; Koch, O.; Grossmann, T.N. Structure-based design of inhibitors of protein-protein interactions: Mimicking peptide binding epitopes. Angew. Chem. Int. Ed. Engl., 2015, 54(31), 8896-8927.
[http://dx.doi.org/10.1002/anie.201412070] [PMID: 26119925]
[89]
Yin, H.; Hamilton, A.D. Terephthalamide derivatives as mimetics of the helical region of Bak peptide target Bcl-xL protein. Bioorg. Med. Chem. Lett., 2004, 14(6), 1375-1379.
[http://dx.doi.org/ 10.1016/j.bmcl.2003.09.096] [PMID: 15006365]
[90]
Antuch, W.; Menon, S.; Chen, Q.Z.; Lu, Y.; Sakamuri, S.; Beck, B.; Schauer-Vukasinović, V.; Agarwal, S.; Hess, S.; Dömling, A. Design and modular parallel synthesis of a MCR derived alpha-helix mimetic protein-protein interaction inhibitor scaffold. Bioorg. Med. Chem. Lett., 2006, 16(6), 1740-1743.
[http://dx.doi.org/ 10.1016/j.bmcl.2005.11.102] [PMID: 16427279]
[91]
Kritzer, J.A. Stapled peptides: Magic bullets in nature’s arsenal. Nat. Chem. Biol., 2010, 6(8), 566-567.
[http://dx.doi.org/ 10.1038/nchembio.407] [PMID: 20644540]
[92]
Walensky, L.D.; Kung, A.L.; Escher, I.; Malia, T.J.; Barbuto, S.; Wright, R.D.; Wagner, G.; Verdine, G.L.; Korsmeyer, S.J. Activation of apoptosis in vivo by a hydrocarbon-stapled BH3 helix. Science, 2004, 305(5689), 1466-1470.
[http://dx.doi.org/10.1126/science.1099191] [PMID: 15353804]
[93]
Stewart, M.L.; Fire, E.; Keating, A.E.; Walensky, L.D. The MCL-1 BH3 helix is an exclusive MCL-1 inhibitor and apoptosis sensitizer. Nat. Chem. Biol., 2010, 6(8), 595-601.
[http://dx.doi.org/ 10.1038/nchembio.391] [PMID: 20562877]
[94]
Tse, C.; Shoemaker, A.R.; Adickes, J.; Anderson, M.G.; Chen, J.; Jin, S.; Johnson, E.F.; Marsh, K.C.; Mitten, M.J.; Nimmer, P.; Roberts, L.; Tahir, S.K.; Xiao, Y.; Yang, X.; Zhang, H.; Fesik, S.; Rosenberg, S.H.; Elmore, S.W. ABT-263: A potent and orally bioavailable Bcl-2 family inhibitor. Cancer Res., 2008, 68(9), 3421-3428.
[http://dx.doi.org/10.1158/0008-5472.CAN-07-5836] [PMID: 18451170]
[95]
Souers, A.J.; Leverson, J.D.; Boghaert, E.R.; Ackler, S.L.; Catron, N.D.; Chen, J.; Dayton, B.D.; Ding, H.; Enschede, S.H.; Fairbrother, W.J.; Huang, D.C.; Hymowitz, S.G.; Jin, S.; Khaw, S.L.; Kovar, P.J.; Lam, L.T.; Lee, J.; Maecker, H.L.; Marsh, K.C.; Mason, K.D.; Mitten, M.J.; Nimmer, P.M.; Oleksijew, A.; Park, C.H.; Park, C.M.; Phillips, D.C.; Roberts, A.W.; Sampath, D.; Seymour, J.F.; Smith, M.L.; Sullivan, G.M.; Tahir, S.K.; Tse, C.; Wendt, M.D.; Xiao, Y.; Xue, J.C.; Zhang, H.; Humerickhouse, R.A.; Rosenberg, S.H.; Elmore, S.W. ABT-199, A potent and selective BCL-2 inhibitor, achieves antitumor activity while sparing platelets. Nat. Med., 2013, 19(2), 202-208.
[http://dx.doi.org/ 10.1038/nm.3048] [PMID: 23291630]
[96]
Qian, J.; Voorbach, M.J.; Huth, J.R.; Coen, M.L.; Zhang, H.; Ng, S.C.; Comess, K.M.; Petros, A.M.; Rosenberg, S.H.; Warrior, U.; Burns, D.J. Discovery of novel inhibitors of Bcl-xL using multiple high-throughput screening platforms. Anal. Biochem., 2004, 328(2), 131-138.
[http://dx.doi.org/10.1016/j.ab.2003.12.034] [PMID: 15113688]
[97]
Real, P.J.; Cao, Y.; Wang, R.; Nikolovska-Coleska, Z.; Sanz-Ortiz, J.; Wang, S.; Fernandez-Luna, J.L. Breast cancer cells can evade apoptosis-mediated selective killing by a novel small molecule inhibitor of Bcl-2. Cancer Res., 2004, 64(21), 7947-7953.
[http://dx.doi.org/10.1158/0008-5472.CAN-04-0945] [PMID: 15520201]
[98]
Hou, X.; Du, J.; Fang, H.; Li, M. 3D-QSAR study on a series of Bcl-2 protein inhibitors using comparative molecular field analysis. Protein Pept. Lett., 2011, 18(5), 440-449.
[http://dx.doi.org/ 10.2174/092986611794927992] [PMID: 21171944]
[99]
Srivastava, A.K.; Srivastava, A.; Jaiswal, M.; Nath, A. QSAR studies on anti-apoptotic Bcl-2 protein inhibitors. J. Saudi Chem. Soc., 2009, 13, 259-262.
[http://dx.doi.org/10.1016/j.jscs. 2009.10.005]
[100]
Böhm, H.J.; Flohr, A.; Stahl, M. Scaffold hopping. Drug Discov. Today. Technol., 2004, 1(3), 217-224.
[http://dx.doi.org/10.1016/j.ddtec.2004.10.009] [PMID: 24981488]


Rights & PermissionsPrintExport Cite as

Article Details

VOLUME: 19
ISSUE: 6
Year: 2019
Page: [457 - 466]
Pages: 10
DOI: 10.2174/1568026619666190304143354
Price: $58

Article Metrics

PDF: 27
HTML: 2