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Drugging the ‘undruggable’ cancer targets
Open accessAbstract
The term 'undruggable' was coined to describe proteins that could not be targeted pharmacologically. However, progress is being made to 'drug' many of these targets, and therefore more appropriate terms might be 'difficult to drug' or 'yet to be drugged'. Many desirable targets in cancer fall into this category, including the RAS and MYC oncogenes, and pharmacologically targeting these intractable proteins is now a key challenge in cancer research that requires innovation and the development of new technologies. In this Viewpoint article, we asked four scientists working in this field for their opinions on the most crucial advances, as well as the challenges and what the future holds for this important area of research.
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“Transcription factors have remained challenging drug targets due to the absence of druggable active sites (14).”
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Cites
Vogelstein, B., Papadopoulos, N., Velculescu, V. E., Zhou, S., Diaz, L. A., & Kinzler, K. W. (2013) · Science · doi:10.1126/science.1235122 · Cited by 7,863
The future of immune checkpoint therapy
Sharma, P., & Allison, J. P. (2015) · Science · doi:10.1126/science.aaa8172 · Cited by 4,878
Selective inhibition of BET bromodomains
Filippakopoulos, P., Qi, J., Picaud, S., Shen, Y., Smith, W. B., Fedorov, O., Morse, E. M., Keates, T., Hickman, T. T., Felletar, I., et al. (2010) · Nature · doi:10.1038/nature09504 · Cited by 4,262
Dang, C. V. (2012) · Cell · doi:10.1016/j.cell.2012.03.003 · Cited by 3,390
Self-citationPeptide therapeutics: current status and future directions
Fosgerau, K., & Hoffmann, T. (2014) · Drug Discovery Today · doi:10.1016/j.drudis.2014.10.003 · Cited by 3,160
AR-V7 and Resistance to Enzalutamide and Abiraterone in Prostate Cancer
Antonarakis, E. S., Lu, C., Wang, H., Luber, B., Nakazawa, M., Roeser, J. C., Chen, Y., Mohammad, T. A., Chen, Y., Fedor, H. L., et al. (2014) · New England Journal of Medicine · doi:10.1056/nejmoa1315815 · Cited by 2,710
K-Ras(G12C) inhibitors allosterically control GTP affinity and effector interactions
Ostrem, J. M., Peters, U., Sos, M. L., Wells, J. A., & Shokat, K. M. (2013) · Nature · doi:10.1038/nature12796 · Cited by 2,557
Self-citationDrugging the undruggable RAS: Mission Possible?
Cox, A. D., Fesik, S. W., Kimmelman, A. C., Luo, J., & Der, C. J. (2014) · Nature Reviews Drug Discovery · doi:10.1038/nrd4389 · Cited by 1,997
Macropinocytosis of protein is an amino acid supply route in Ras-transformed cells
Commisso, C., Davidson, S. M., Soydaner-Azeloglu, R. G., Parker, S. J., Kamphorst, J. J., Hackett, S., Grabocka, E., Nofal, M., Drebin, J. A., Thompson, C. B., et al. (2013) · Nature · doi:10.1038/nature12138 · Cited by 1,683
Emerging mechanisms of resistance to androgen receptor inhibitors in prostate cancer
Watson, P. A., Arora, V. K., & Sawyers, C. L. (2015) · Nature Reviews Cancer · doi:10.1038/nrc4016 · Cited by 1,536
Induced protein degradation: an emerging drug discovery paradigm
Lai, A. C., & Crews, C. M. (2017) · Nature Reviews Drug Discovery · doi:10.1038/nrd.2016.211 · Cited by 1,486
Oncogene ablation-resistant pancreatic cancer cells depend on mitochondrial function
Viale, A., Pettazzoni, P., Lyssiotis, C. A., Ying, H., Sánchez, N., Marchesini, M., Carugo, A., Green, T., Seth, S., Giuliani, V., et al. (2014) · Nature · doi:10.1038/nature13611 · Cited by 1,259
Targeting MYC dependence in cancer by inhibiting BET bromodomains
Mertz, J. A., Conery, A. R., Bryant, B. M., Sandy, P., Balasubramanian, S., Mele, D. A., Bergeron, L., & Sims, R. J. (2011) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1108190108 · Cited by 1,145
Is NF-κB a good target for cancer therapy? Hopes and pitfalls
Baud, V., & Karin, M. (2008) · Nature Reviews Drug Discovery · doi:10.1038/nrd2781 · Cited by 1,084
The MCL1 inhibitor S63845 is tolerable and effective in diverse cancer models
Kotschy, A., Szlavik, Z., Murray, J., Davidson, J., Maragno, A. L., Le Toumelin-Braizat, G., Chanrion, M., Kelly, G. L., Gong, J.-N., Moujalled, D. M., et al. (2016) · Nature · doi:10.1038/nature19830 · Cited by 1,047
Ras superfamily GEFs and GAPs: validated and tractable targets for cancer therapy?
Vigil, D., Cherfils, J., Rossman, K. L., & Der, C. J. (2010) · Nature reviews. Cancer · doi:10.1038/nrc2960 · Cited by 850
Modelling Myc inhibition as a cancer therapy
Soucek, L., Whitfield, J. R., Martins, C. P., Finch, A. J., Murphy, D. J., Sodir, N. M., Karnezis, A. N., Swigart, L. B., Nasi, S., & Evan, G. I. (2008) · Nature · doi:10.1038/nature07260 · Cited by 846
Self-citationStephen, A. G., Esposito, D., Bagni, R. K., & McCormick, F. (2014) · Cancer Cell · doi:10.1016/j.ccr.2014.02.017 · Cited by 795
Selective inhibition of oncogenic KRAS output with small molecules targeting the inactive state
Patricelli, M. P., Janes, M. R., Li, L.-S., Hansen, R., Peters, U., Kessler, L. V., Chen, Y., Kucharski, J. M., Feng, J., Ely, T., et al. (2016) · Cancer Discovery · doi:10.1158/2159-8290.cd-15-1105 · Cited by 759
Mechanisms of Disease: oncogene addiction—a rationale for molecular targeting in cancer therapy
Weinstein, I. B., & Joe, A. K. (2006) · Nature Clinical Practice Oncology · doi:10.1038/ncponc0558 · Cited by 739
Yap1 Activation Enables Bypass of Oncogenic Kras Addiction in Pancreatic Cancer
Kapoor, A., Yao, W., Ying, H., Hua, S., Liewen, A., Wang, Q., Zhong, Y., Wu, C.-J., Sadanandam, A., Hu, B., et al. (2014) · Cell · doi:10.1016/j.cell.2014.06.003 · Cited by 716 · cited 1×
“Studies by Ronald DePinho’s group 47 showed that some tumours induced by Kras G12D undergo spontaneous relapse following Kras G12D ablation owing to amplification and overexpression of the Yes-associated protein 1 ( Yap1 ) transcriptional coactivator, which drives Kras G12D -independent tumour…”
A novel cereblon modulator recruits GSPT1 to the CRL4CRBN ubiquitin ligase
Matyskiela, M. E., Lu, G., Ito, T., Pagarigan, B., Lu, C.-C., Miller, K., Fang, W., Wang, N.-Y., Nguyen, D., Houston, J., et al. (2016) · Nature · doi:10.1038/nature18611 · Cited by 701
Allele-specific inhibitors inactivate mutant KRAS G12C by a trapping mechanism
Lito, P., Solomon, M., Li, L.-S., Hansen, R., & Rosen, N. (2016) · Science · doi:10.1126/science.aad6204 · Cited by 691
Targeted protein degradation by PROTACs
Neklesa, T. K., Winkler, J. D., & Crews, C. M. (2017) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2017.02.027 · Cited by 599
Massarelli, E., Varella‐Garcia, M., Tang, X., Xavier, A. C., Ozburn, N. C., Liu, D. D., Bekele, B. N., Herbst, R. S., & Wistuba, I. I. (2007) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-06-3043 · Cited by 594
Stabilization of N-Myc Is a Critical Function of Aurora A in Human Neuroblastoma
Otto, T., Horn, S., Brockmann, M., Eilers, U., Schüttrumpf, L., Popov, N., Kenney, A. M., Schulte, J. H., Beijersbergen, R. L., Christiansen, H., et al. (2009) · Cancer Cell · doi:10.1016/j.ccr.2008.12.005 · Cited by 576
Reversible targeting of noncatalytic cysteines with chemically tuned electrophiles
Serafimova, I. M., Pufall, M. A., Krishnan, S., Duda, K., Cohen, M. S., Maglathlin, R. L., McFarland, J. M., Miller, R. M., Frödin, M., & Taunton, J. (2012) · Nature Chemical Biology · doi:10.1038/nchembio.925 · Cited by 505
Farrell, A. S., & Sears, R. C. (2014) · Cold Spring Harbor Perspectives in Medicine · doi:10.1101/cshperspect.a014365 · Cited by 468
Shimizu, T., Tolcher, A. W., Papadopoulos, K. P., Beeram, M., Rasco, D. W., Smith, L. S., Gunn, S., Smetzer, L., Mays, T. A., Kaiser, B., et al. (2012) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-11-2381 · Cited by 431
Frye, S. V. (2010) · Nature Chemical Biology · doi:10.1038/nchembio.296 · Cited by 381
Verdine, G. L., & Walensky, L. D. (2007) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-07-2184 · Cited by 374
Two Hundred Years of Cancer Research
DeVita, V. T., & Rosenberg, S. A. (2012) · New England Journal of Medicine · doi:10.1056/nejmra1204479 · Cited by 331
McCormick, F. (2015) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-14-2662 · Cited by 320
Inhibition of Myc family proteins eradicates KRas-driven lung cancer in micePreprint
Soucek, L., Whitfield, J. R., Sodir, N. M., Massó-Vallés, D., Serrano, E., Karnezis, A. N., Swigart, L. B., & Evan, G. I. (2013) · Genes & Development · doi:10.1101/gad.205542.112 · Cited by 310
Self-citationStrategies to Inhibit Myc and Their Clinical Applicability
Whitfield, J. R., Beaulieu, M.-È., & Soucek, L. (2017) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2017.00010 · Cited by 303
Self-citationDrugging MYCN through an Allosteric Transition in Aurora Kinase A
Gustafson, W. C., Meyerowitz, J., Nekritz, E. A., Chen, J., Benes, C. H., Charron, E., Simonds, E. F., Seeger, R. C., Matthay, K. K., Hertz, N. T., et al. (2014) · Cancer Cell · doi:10.1016/j.ccr.2014.07.015 · Cited by 284
Self-citationMultivalent Small-Molecule Pan-RAS Inhibitors
Welsch, M., Kaplan, A. R., Chambers, J. M., Stokes, M. E., Bos, P. H., Zask, A., Zhang, Y., Sánchez-Martín, M., Badgley, M. A., Huang, C., et al. (2017) · Cell · doi:10.1016/j.cell.2017.02.006 · Cited by 282
A Small Molecule RAS-Mimetic Disrupts RAS Association with Effector Proteins to Block Signaling
Divakar, S. K. A., Carpio, R. V., Dutta, K., Baker, S. J., Cosenza, S. C., Basu, I., Gupta, Y. K., Reddy, M. V. R., Ueno, L. A., Hart, J. R., et al. (2016) · Cell · doi:10.1016/j.cell.2016.03.045 · Cited by 278
Self-citationOksenberg, D., Dufu, K., Patel, M. P., Chuang, C.-Y., Li, Z., Xu, Q. R., Silva‐Garcia, A., Zhou, C., Hutchaleelaha, A., Patskovska, L. N., et al. (2016) · British Journal of Haematology · doi:10.1111/bjh.14214 · Cited by 244
Multiple Independent Binding Sites for Small-Molecule Inhibitors on the Oncoprotein c-Myc
Hammoudeh, D. I., Follis, A. V., Prochownik, E. V., & Metallo, S. J. (2009) · Journal of the American Chemical Society · doi:10.1021/ja900616b · Cited by 239
Drugging Undruggable Molecular Cancer Targets
Lazo, J. S., & Sharlow, E. R. (2015) · The Annual Review of Pharmacology and Toxicology · doi:10.1146/annurev-pharmtox-010715-103440 · Cited by 234
Proteolysis-Targeting Chimeras: Induced Protein Degradation as a Therapeutic Strategy
Ottis, P., & Crews, C. M. (2017) · ACS Chemical Biology · doi:10.1021/acschembio.6b01068 · Cited by 228
Targeting the ubiquitin–proteasome system for cancer therapy
Shen, M., Schmitt, S. M., Buac, D., & Dou, Q. P. (2013) · Expert Opinion on Therapeutic Targets · doi:10.1517/14728222.2013.815728 · Cited by 204
Structural basis of N-Myc binding by Aurora-A and its destabilization by kinase inhibitors
Richards, M. W., Burgess, S. G., Poon, E., Carstensen, A., Eilers, M., Chesler, L., & Bayliss, R. W. (2016) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1610626113 · Cited by 189
Expanding the Number of ‘Druggable’ Targets: Non‐Enzymes and Protein–Protein Interactions
Makley, L. N., & Gestwicki, J. E. (2012) · Chemical Biology & Drug Design · doi:10.1111/cbdd.12066 · Cited by 183
Nanoparticle-siRNA: A potential cancer therapy?
Young, S. W. S., Stenzel, M. H., & Jia-Lin, Y. (2015) · Critical Reviews in Oncology/Hematology · doi:10.1016/j.critrevonc.2015.10.015 · Cited by 161
Small-molecule inhibitors of the Myc oncoprotein
Fletcher, S., & Prochownik, E. V. (2014) · Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanisms · doi:10.1016/j.bbagrm.2014.03.005 · Cited by 160
Targeting disordered proteins with small molecules using entropy
Heller, G. T., Sormanni, P., & Vendruscolo, M. (2015) · Trends in Biochemical Sciences · doi:10.1016/j.tibs.2015.07.004 · Cited by 107
Single Enantiomer of YK-4-279 Demonstrates Specificity in Targeting the Oncogene EWS-FLI1
Barber-Rotenberg, J. S., Selvanathan, S. P., Kong, Y., Erkizan, H. V., Snyder, T. M., Hong, S. P., Kobs, C. L., South, N. L., Summer, S., Monroe, P. J., et al. (2012) · Oncotarget · doi:10.18632/oncotarget.454 · Cited by 101
How to unleash mitochondrial apoptotic blockades to kill cancers?
Deng, J. (2016) · Acta Pharmaceutica Sinica B · doi:10.1016/j.apsb.2016.08.005 · Cited by 65
Targeting the undruggable: immunotherapy meets personalized oncology in the genomic era
Martin, S. D., Coukos, G., Holt, R. A., & Nelson, B. H. (2015) · Annals of Oncology · doi:10.1093/annonc/mdv382 · Cited by 50
MYC, Metabolic Synthetic Lethality, and Cancer
Hsieh, A. L., & Dang, C. V. (2016) · Recent results in cancer research/Recent Results in Cancer Research · doi:10.1007/978-3-319-42118-6_4 · Cited by 38
Self-citationTaking a Back Door to Target Myc
Evan, G. I. (2012) · Science · doi:10.1126/science.1217819 · Cited by 34
Belchis, D., Tseng, L., Gniadek, T. J., Haley, L. M., Lokhandwala, P. M., Illei, P. B., Gocke, C. D., Forde, P. M., Brahmer, J. R., Askin, F. B., et al. (2016) · Oncotarget · doi:10.18632/oncotarget.9931 · Cited by 28
Zhang, C., Pei, J., Kumar, D., Sakabe, I., Boudreau, H. E., Gokhale, P. C., & Kasid, U. N. (2006) · Humana Press eBooks · doi:10.1385/1-59745-208-4:163 · Cited by 25
Protein Chip for Detection of DNA Mutations
Zhang, X., & Bi, L. (2007) · Methods in molecular biology · doi:10.1007/978-1-59745-304-2_11 · Cited by 22
aBETting therapeutic resistance by Wnt signaling
Engelke, C. G., & Chinnaiyan, A. M. (2015) · Cell Research · doi:10.1038/cr.2015.127 · Cited by 11
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Metadata
- Authors
- Dang, C. V., Reddy, E. P., Shokat, K. M., & Soucek, L.
- Affiliations
- The Wistar Institute (US)
- Icahn School of Medicine at Mount Sinai (US)
- Howard Hughes Medical Institute (US)
- Institució Catalana de Recerca i Estudis Avançats (ES)
- Corresponding author
- Dang, Chi V.
- Reddy, E. Premkumar
- Shokat, Kevan M.
- Soucek, Laura
- Venue
- Nature Reviews Cancer
- Published
- 2017-06-23
- Volume
- 17
- Issue
- 8
- Pages
- 502-508
- ISSN
- 1474-175X (ISSN-L)
- 1474-1768
- PMC
- PMC5945194
- OpenAlex
- W2692768525
- Cited by
- 927
- References
- 57
- Citations by year
- 2026: 93 · 2025: 113 · 2024: 125 · 2023: 110 · 2022: 121 · 2021: 121 · 2020: 113 · 2019: 63 · 2018: 58 · 2017: 10
- FWCI
- 6.26
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature reviews. Cancer (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- National Cancer Institute (R01CA057341, R01CA158209, R01CA051497)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Degradation and Inhibitors
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer Mechanisms and Therapy
- Keywords
- oncogenic Ras, MYC oncogene, oncogene targeting, anticancer drug development
- MeSH terms
- Antineoplastic Agents, Humans, Neoplasms, Receptors, Androgen, Oncogene Proteins, Fusion, Proto-Oncogene Proteins c-myc, NF-kappa B, ras Proteins, Proto-Oncogene Proteins c-myb, Drug Discovery, Molecular Targeted Therapy
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