REFERENCES AND NOTES
1. A. D. Cox, S. W. Fesik, A. C. Kimmelman, J. Luo, C. J. Der,
Nat. Rev. Drug Discov. 13, 828–851 (2014).
2. A. G. Stephen, D. Esposito, R. K. Bagni, F. McCormick, Cancer
Cell 25, 272–281 (2014).
3. J. Spiegel, P. M. Cromm, G. Zimmermann, T. N. Grossmann,
H. Waldmann, Nat. Chem. Biol. 10, 613–622 (2014).
4. H. Thompson, Nat. Med. 19, 949–950 (2013).
5. A. D. Cox, C. J. Der, Small GTPases 1, 2–27 (2010).
6. F. D. Tsai et al., Proc. Natl. Acad. Sci. U.S.A. 112, 779–784
7. D. Vigil, J. Cherfils, K. L. Rossman, C. J. Der, Nat. Rev. Cancer
10, 842–857 (2010).
8. J. S. Lazo, E. R. Sharlow, Annu. Rev. Pharmacol. Toxicol. 56,
9. Y. Pylayeva-Gupta, E. Grabocka, D. Bar-Sagi, Nat. Rev. Cancer
11, 761–774 (2011).
10. K. L. Bryant, J. D. Mancias, A. C. Kimmelman, C. J. Der, Trends
Biochem. Sci. 39, 91–100 (2014).
11. A. D. Cox, C. J. Der, M. R. Philips, Clin. Cancer Res. 21,
12. I. M. Ahearn, K. Haigis, D. Bar-Sagi, M. R. Philips, Nat. Rev. Mol.
Cell Biol. 13, 39–51 (2011).
13. A. E. Karnoub, R. A. Weinberg, Nat. Rev. Mol. Cell Biol. 9,
14. D. van der Hoeven et al., Mol. Cell. Biol. 33, 237–251
15. K.-J. Cho et al., Mol. Cell. Biol. 36, 363–374 (2015).
16. M. Schmick et al., Cell 157, 459–471 (2014).
17. G. Zimmermann et al., Nature 497, 638–642 (2013).
18. B. Papke et al., Nat. Commun. 7, 11360 (2016).
19. M. B. Ryan, C. J. Der, A. Wang-Gillam, A. D. Cox, Trends Cancer
1, 183–198 (2015).
20. K.-K. Wong, J. A. Engelman, L. C. Cantley, Curr. Opin. Genet.
Dev. 20, 87–90 (2010).
21. A. K. Witkiewicz et al., Cell Rep. 16, 2017–2031 (2016).
22. S. H. Chen et al., Cancer Discov. 6, 300–315 (2016).
23. S. A. Foster et al., Cancer Cell 29, 477–493 (2016).
24. C. Guerra, M. Barbacid, Mol. Oncol. 7, 232–247 (2013).
25. A. A. Samatar, P. I. Poulikakos, Nat. Rev. Drug Discov. 13,
26. S. J. Heidorn et al., Cell 140, 209–221 (2010).
27. P. I. Poulikakos, C. Zhang, G. Bollag, K. M. Shokat, N. Rosen,
Nature 464, 427–430 (2010).
28. S.-B. Peng et al., Cancer Cell 28, 384–398 (2015).
29. C. Zhang et al., Nature 526, 583–586 (2015).
30. J. S. Duncan et al., Cell 149, 307–321 (2012).
31. S. K. Athuluri-Divakar et al., Cell 165, 643–655 (2016).
32. D. A. Ritt et al., Mol. Cell 64, 875–887 (2016).
33. W. G. Kaelin Jr., Nat. Rev. Cancer 5, 689–698 (2005).
34. J. Downward, Clin. Cancer Res. 21, 1802–1809 (2015).
35. T. Wang et al., Cell 168, 1–14 (2017).
36. D. Hanahan, R. A. Weinberg, Cell 144, 646–674
37. D. Zeitouni, Y. Pylayeva-Gupta, C. J. Der, K. L. Bryant, Cancers
8, 45–22 (2016).
38. T. Maurer et al., Proc. Natl. Acad. Sci. U.S.A. 109, 5299–5304
39. S. Yang et al., Genes Dev. 25, 717–729 (2011).
40. D. J. Klionsky et al, Autophagy 12, 1–222 (2016).
41. H. Ying et al., Cell 149, 656–670 (2012).
42. J. Son et al., Nature 496, 101–105 (2013).
43. E. F. Pai et al., Nature 341, 209–214 (1989).
44. Q. Sun et al., Angew. Chem. Int. Ed. Engl. 51, 6140–6143
45. F. Shima et al., Proc. Natl. Acad. Sci. U.S.A. 110, 8182–8187
46. J. M. Ostrem, U. Peters, M. L. Sos, J. A. Wells, K. M. Shokat,
Nature 503, 548–551 (2013).
47. J. C. Hunter et al., Proc. Natl. Acad. Sci. U.S.A. 111, 8895–8900
48. P. Lito, M. Solomon, L.-S. Li, R. Hansen, N. Rosen, Science 351,
49. M. P. Patricelli et al., Cancer Discov. 6, 316–329 (2016).
C.J.D. is on the Scientific Advisory Boards of Warp Drive Bio, a
company developing therapeutics for proteins that cannot be
targeted by conventional drug discovery approaches, and Kyras
Therapeutics, a company developing RAS-targeted drugs. C.J.D. is
also a paid consultant for Astex Pharmaceutics, Novartis, LifeSci
Advisors, and Cullinan Pharmaceuticals.
Waste disposal—An attractive
strategy for cancer therapy
Jemilat Salami1 and Craig M. Crews1,2,3*
Targeted therapies for cancer are typically small molecules or monoclonal antibodies
that act by inhibiting the activity of specific proteins that drive tumor growth.
Although many of these drugs are effective in cancer patients, the response is often
not durable because tumor cells develop resistance to the drugs. Another limitation of
this strategy is that not all oncogenic driver proteins are “druggable” enzymes or receptors with
activities that can be inhibited. Here we describe an alternative approach to targeted therapy
that is based on co-opting the cellular quality-control machinery—the ubiquitin-proteasome
system—to remove specific cancer-causing proteins from the cell. We first discuss examples of
existing cancer drugs that work by degrading specific proteins and then review recent
progress in the rational design and preclinical testing of small molecules that induce
selective degradation of specific target proteins.
Cancer continues to be a leading global health problem; it has been estimated that by 2025 there will be nearly 20 million ew cancer cases diagnosed each year (1). Notable progress is being made in cancer
drug development, particularly in the areas of immunotherapy and targeted therapy, but the enormity of the cancer problem requires a variety of
therapeutic strategies. Many targeted therapies
for cancer are small molecules or monoclonal
antibodies that inhibit the activity of proteins
driving tumor growth. Tumor cells often develop
resistance to these drugs through overexpression
of the target protein and/or through the acquisition of new mutations in the target protein that
allow it to escape the inhibitory effect of the drug.
Over the past 15 years, researchers have be-
gun to explore an alternative therapeutic ap-
proach that aims to control protein function by
regulating protein expression levels rather than
activities. These efforts to harness controlled
proteostasis as a therapeutic strategy evolved
from the discovery that proteasome inhibitors
that block protein degradation have anticancer
activity. Carfilzomib and bortezomib are two ex-
amples of such proteasome inhibitors approved
by the U.S. Food and Drug Administration (FDA)
for the treatment of multiple myeloma (MM)
(2). Investigators have explored other ways in
which the ubiquitin-proteasome system (UPS)
can be manipulated to stabilize or promote the
degradation of disease-causing proteins (Table 1).
For example, efforts have been made to disrupt
the interaction between proteins and the ubi-
quitin E3 ligases responsible for their degradation
(3). The interaction between the tumor suppres-
sor p53 and its ubiquitin E3 ligase, MDM2 (mouse
double minute 2 homolog), has been an attract-
ive oncology target: A potent inhibitor of this in-
teraction (RG7112) was found to kill wild-type p53-
expressing cancer cells and to inhibit tumor growth
in preclinical models of cancer. A reduction in the
levels of oncoproteins can also be achieved by
inhibiting enzymes that function to stabilize these
proteins (3). For example, inhibition of USP7 (the
ubiquitin-specific protease 7), a deubiquitinating
enzyme (DUB) that deubiquitinates and stabilizes
MDM2, reduces MDM2 levels and consequently
increases p53 levels. To that end, the USP7 in-
hibitor P5091 has shown promising antitumor
activity in MM xenograft models (4).
More recently, interest has focused on directly using the UPS to induce degradation of
specific target proteins, especially proteins for
which there are no established DUBs or E3
ligases. These newer strategies involve the pharmacological hijacking of the cellular quality-control system to posttranslationally eliminate
disease-causing proteins (Table 1). In this Review, we discuss the initial applications of this
concept of targeted protein degradation to achieve
controlled proteostasis and the strategies employed to generate protein degraders. We highlight the progress achieved to date, as well as the
some of the challenges inherent in this approach.
The limitations of
In this postgenomic era, a better understanding
of the molecular drivers of cancer has led to the
development of several successful cancer therapies that inhibit the activity of enzymes such
as protein kinases (e.g., imatinib, erlotinib, and
palbociclib), histone deacetylases (e.g., belinostat),
and poly(ADP-ribose) polymerase (e.g., olaparib).
These small-molecule inhibitors generally work
by occupying a binding pocket or active site,
resulting in the loss of protein function. However,
given that most enzyme inhibitors bind noncovalently (and thus reversibly), high drug concentrations must be maintained to ensure active-site
occupancy and to sustain the clinical benefit (5).
This is understood as an “occupancy-driven” pharmacological paradigm: one that necessitates that
1Department of Molecular, Cellular and Developmental
Biology, Yale University, New Haven, CT 06520, USA.
2Department of Chemistry, Yale University, New Haven, CT
06520, USA. 3Department of Pharmacology, Yale University,
New Haven, CT 06520, USA.
*Corresponding author. Email: email@example.com