Please d oC hn eo mt Ca do mj u ms t margins
Page 4 of 4
COMMUNICATION
Journal Name
7
6, 15200–15209; (b) A. Cuesta and J. Taunton, Annu. Rev. Biochem., 2019, 88,
DOI: 10.1146/annurev-biochem-061516-044805.
our CuAAC 2C-PS technique, the staple was functionalised with
a suitable electrophile for forming a covalent cross-linking with
the target protein upon binding. We validated this approach
using an STP ester-functionalised stapled peptide targeting the
oncogenic protein MDM2: the lead peptide P1-2
demonstrated complete covalent complex formation and nM
inhibition to MDM2.
5
DOI: 10.1039/C9CC04022F
8
9
G. Platzer, M. Okon and L. P. McIntosh, J. Biomol. NMR, 2014, 60, 109–129.
A. Burgess, K. M. Chia, S. Haupt, D. Thomas, Y. Haupt and E. Lim, Front. Oncol.,
2016, 6, 1–7.
(a) Y. Haupt, R. Maya, A. Kazaz and M. Oren, Nature, 1997, 387, 296–299; (b)
R. Honda, H. Tanaka and H. Yasuda, FEBS Lett., 1997, 420, 25–27.
(a) S. Shangary and S. Wang, Clin. Cancer Res., 2008, 14, 5318–5324; (b) F. S.
Leach, T. Tokino, P. Meltzer, M. Burrell, J. D. Oliner, S. Smith, D. E. Hill, D.
Sidransky, K. W. Kinzler and B. Vogelstein, Cancer Res., 1993, 53, 2231–4; (c) J.
D. Oliner, K. W. Kinzler, P. S. Meltzer, D. L. George and B. Vogelstein, Nature,
1
1
0
1
Importantly, the results and concept of our study would
expedite the development of stapled peptide covalent
inhibitors by removing the need to synthesise the peptides
anew for every sequence and requiring less demanding
conditions on the electrophile. We envision that targeting
proteins with low turnover rates would gain the most benefit
1
992, 358, 80–83.
1
2
(a) V. Tisato, R. Voltan, A. Gonelli, P. Secchiero and G. Zauli, J. Hematol. Oncol.,
2
2
017, 10, 133; (b) D. Nguyen, W. Liao, S. X. Zeng and H. Lu, Pharmacol. Ther.,
017, 178, 92–108; (c) A. Aguilar, J. Lu, L. Liu, D. Du, D. Bernard, D. McEachern,
1
a,7a
from using this strategy.
A further advantage of using the
S. Przybranowski, X. Li, R. Luo, B. Wen, D. Sun, H. Wang, J. Wen, G. Wang, Y.
Zhai, M. Guo, D. Yang and S. Wang, J. Med. Chem., 2017, 60, 2819–2839.
(a) D. E. Scott, A. R. Bayly, C. Abell and J. Skidmore, Nat. Rev. Drug Discov.,
CuAAC 2C-PS technique is that extra functionalisation may be
achieved by appending a second functional handle to the
staple and hence further enhance the capability of peptide
inhibitors.
The research was supported by grants from the
Engineering and Physical Sciences Research Council,
Biotechnology and Biological Sciences Research Council,
Medical Research Council and Royal Society. JC and JI would
like to thank Trinity College, Cambridge for funding. YST and
CSV would like to thank A*STAR (IAF-PP H17/01/a0/010) for
support.
1
1
3
4
2
1
016, 15, 533–550; (b) J. A. Wells and C. L. McClendon, Nature, 2007, 450,
001–1009.
(a) L. D. Walensky and G. H. Bird, J. Med. Chem., 2014, 57, 6275–6288; (b) Y. H.
Lau, P. de Andrade, S.-T. Quah, M. Rossmann, L. Laraia, N. Sköld, T. J. Sum, P. J.
E. Rowling, T. L. Joseph, C. Verma, M. Hyvönen, L. S. Itzhaki, A. R.
Venkitaraman, C. J. Brown, D. P. Lane and D. R. Spring, Chem. Sci., 2014, 5,
1
804–1809; (c) Y. H. Lau, P. de Andrade, Y. Wu and D. R. Spring, Chem. Soc.
Rev., 2015, 44, 91–102; (d) J. Iegre, J. S. Gaynord, N. S. Robertson, H. F. Sore,
M. Hyvönen and D. R. Spring, Adv. Ther., 2018, 1, 1800052.
1
5
(a) F. Bernal, A. F. Tyler, S. J. Korsmeyer, L. D. Walensky and G. L. Verdine, J.
Am. Chem. Soc., 2007, 129, 2456–2457; (b) Y. S. Chang, B. Graves, V.
Guerlavais, C. Tovar, K. Packman, K.-H. To, K. A. Olson, K. Kesavan, P.
Gangurde, A. Mukherjee, T. Baker, K. Darlak, C. Elkin, Z. Filipovic, F. Z. Qureshi,
H. Cai, P. Berry, E. Feyfant, X. E. Shi, J. Horstick, D. A. Annis, A. M. Manning, N.
Fotouhi, H. Nash, L. T. Vassilev and T. K. Sawyer, Proc. Natl. Acad. Sci. U. S. A.,
2013, 110, E3445–E3454; (c) C. J. Brown, S. T. Quah, J. Jong, A. M. Goh, P. C.
Chiam, K. H. Khoo, M. L. Choong, M. A. Lee, L. Yurlova, K. Zolghadr, T. L.
Joseph, C. S. Verma and D. P. Lane, ACS Chem. Biol., 2013, 8, 506–512; (d) Y. H.
Lau, Y. Wu, M. Rossmann, B. X. Tan, P. de Andrade, Y. S. Tan, C. Verma, G. J.
McKenzie, A. R. Venkitaraman, M. Hyvönen and D. R. Spring, Angew. Chem.
Int. Ed., 2015, 54, 15410–15413; (e) K. Hu, F. Yin, M. Yu, C. Sun, J. Li, Y. Liang,
W. Li, M. Xie, Y. Lao, W. Liang and Z.-G. Li, Theranostics, 2017, 7, 4566–4576;
(f) X. Li, W. D. Tolbert, H.-G. Hu, N. Gohain, Y. Zou, F. Niu, W.-X. He, W. Yuan,
J.-C. Su, M. Pazgier and W. Lu, Chem. Sci., 2019, 10, 1522–1530.
Conflicts of interest
There are no conflicts to declare.
Notes and references
‡
Due to the instability of MDM2 in the assay, data for time-points beyond 120
minutes were not obtained.
1
(a) T. A. Baillie, Angew. Chem. Int. Ed., 2016, 55, 13408–13421; (b) M.
Gehringer and S. A. Laufer, J. Med. Chem., 2019, DOI:
1
0.1021/acs.jmedchem.8b01153; (c) E. Anscombe, E. Meschini, R. Mora-Vidal,
16 C. Hoppmann and L. Wang, Chem. Commun., 2016, 52, 5140–5143.
17 Z. Xiang, H. Ren, Y. S. Hu, I. Coin, J. Wei, H. Cang and L. Wang, Nat. Methods,
2013, 10, 885–888.
18 Y. H. Lau, Y. Wu, P. De Andrade, W. R. J. D. Galloway and D. R. Spring, Nat.
Protoc., 2015, 10, 585–594.
S. R. Wedge, J. A. Endicott, R. J. Griffin, M. P. Martin, D. Staunton, M.
Geitmann, U. H. Danielson, W. A. Stanley, L. Z. Wang, T. Reuillon, B. T. Golding,
C. Cano, D. R. Newell and M. E. M. Noble, Chem. Biol., 2015, 22, 1159–1164;
(d) S. E. Dalton, L. Dittus, D. A. Thomas, M. A. Convery, J. Nunes, J. T. Bush, J. P.
Evans, T. Werner, M. Bantscheff, J. A. Murphy and S. Campos, J. Am. Chem.
Soc., 2018, 140, 932–939; (e) T. Tamura, T. Ueda, T. Goto, T. Tsukidate, Y.
Shapira, Y. Nishikawa, A. Fujisawa and I. Hamachi, Nat. Commun., 2018, 9,
19 Y. S. Tan, D. P. Lane and C. S. Verma, Drug Discov. Today, 2016, 21, 1642–
1653.
20 M. Pazgier, M. Liu, G. Zou, W. Yuan, C. Li, C. Li, J. Li, J. Monbo, D. Zella, S. G.
Tarasov and W. Lu, Proc. Natl. Acad. Sci. U. S. A., 2009, 106, 4665–4670.
21 J. Dong, L. Krasnova, M. G. Finn and K. Barry Sharpless, Angew. Chem. Int. Ed.,
2014, 53, 9430–9448.
22 (a) N. N. Gushwa, S. Kang, J. Chen and J. Taunton, J. Am. Chem. Soc., 2012,
134, 20214–20217; (b) A. J. Brouwer, A. Jonker, P. Werkhoven, E. Kuo, N. Li, N.
Gallastegui, J. Kemmink, B. I. Florea, M. Groll, H. S. Overkleeft and R. M. J.
Liskamp, J. Med. Chem., 2012, 55, 10995–11003; (c) N. P. Grimster, S.
Connelly, A. Baranczak, J. Dong, L. B. Krasnova, K. B. Sharpless, E. T. Powers, I.
A. Wilson and J. W. Kelly, J. Am. Chem. Soc., 2013, 135, 5656–5668; (d) Q.
Zhao, X. Ouyang, X. Wan, K. S. Gajiwala, J. C. Kath, L. H. Jones, A. L. Burlingame
and J. Taunton, J. Am. Chem. Soc., 2017, 139, 680–685.
1
870; (f) M. J. Evans, A. Saghatelian, E. J. Sorensen and B. F. Cravatt, Nat.
Biotechnol., 2005, 23, 1303–1307; (g) M. J. Evans, G. M. Morris, J. Wu, A. J.
Olson, E. J. Sorensen and B. F. Cravatt, Mol. Biosyst., 2007, 3, 495; (h) G. Akçay,
M. A. Belmonte, B. Aquila, C. Chuaqui, A. W. Hird, M. L. Lamb, P. B. Rawlins, N.
Su, S. Tentarelli, N. P. Grimster and Q. Su, Nat. Chem. Biol., 2016, 12, 931–936.
A. J. T. Smith, X. Zhang, A. G. Leach and K. N. Houk, J. Med. Chem., 2009, 52,
2
3
2
25–233.
G. Sachs, J. M. Shin and C. W. Howden, Aliment. Pharmacol. Ther., 2006, 23, 2–
8
.
4
5
6
T. Barf and A. Kaptein, J. Med. Chem., 2012, 55, 6243–6262.
R. Lonsdale and R. A. Ward, Chem. Soc. Rev., 2018, 47, 3816–3830.
(a) S. M. Marino and V. N. Gladyshev, J. Mol. Biol., 2010, 404, 902–916; (b) D.
A. Shannon and E. Weerapana, Curr. Opin. Chem. Biol., 2015, 24, 18–26; (c) S.
Wu, H. Luo, H. Wang, W. Zhao, Q. Hu and Y. Yang, Biochem. Biophys. Res.
Commun., 2016, 478, 1268–1273; (d) R. Lagoutte, R. Patouret and N.
Winssinger, Curr. Opin. Chem. Biol., 2017, 39, 54–63.
23 S. M. Hacker, K. M. Backus, M. R. Lazear, S. Forli, B. E. Correia and B. F. Cravatt,
Nat. Chem., 2017, 9, 1181–1190.
24 M. Ahn, E. De Genst, G. S. Kaminski Schierle, M. Erdelyi, C. F. Kaminski, C. M.
Dobson and J. R. Kumita, PLoS One, 2012, 7, e50192.
25 J. Singh, R. C. Petter, T. A. Baillie and A. Whitty, Nat. Rev. Drug Discov., 2011,
1
0, 307–317.
4
| J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 20xx
Please do not adjust margins