Page 5 of 6
ACS Medicinal Chemistry Letters
General experimental information; full synthetic procedures
1
2
3
4
5
6
7
8
and characterisation data for all new compounds; NMR and
LC-MS data. Experimental procedures for cell culture, PBMC
isolation from blood, degradation assay, Western blotting and
cytokine analysis.
6.
Qin, J.; Jiang, Z.; Qian, Y.; Casanova, J. L.; Li, X.,
IRAK4 kinase activity is redundant for interleukin-1 (IL-1)
receptor-associated kinase phosphorylation and IL-1
responsiveness. The Journal of biological chemistry 2004, 279
(25), 26748-53.
All animal studies were ethically reviewed and carried out in
accordance with Animals (Scientific Procedures) Act 1986 and
the GSK Policy on the Care, Welfare and Treatment of
Animals.
7.
Cushing, L.; Stochaj, W.; Siegel, M.; Czerwinski,
R.; Dower, K.; Wright, Q.; Hirschfield, M.; Casanova, J. L.;
Picard, C.; Puel, A.; Lin, L. L.; Rao, V. R., Interleukin 1/Toll-
like receptor-induced autophosphorylation activates interleukin
1 receptor-associated kinase 4 and controls cytokine induction
in a cell type-specific manner. The Journal of biological
chemistry 2014, 289 (15), 10865-75.
9
AUTHOR INFORMATION
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Corresponding Author
ORCID
8.
Wang, Z.; Wesche, H.; Stevens, T.; Walker, N.; Yeh,
W. C., IRAK-4 inhibitors for inflammation. Current topics in
medicinal chemistry 2009, 9 (8), 724-37.
9.
Chaudhary, D.; Robinson, S.; Romero, D. L., Recent
Niall Anderson: 0000-0001-8403-9698
advances in the discovery of small molecule inhibitors of
interleukin-1 receptor-associated kinase 4 (IRAK4) as a
therapeutic target for inflammation and oncology disorders.
Journal of medicinal chemistry 2015, 58 (1), 96-110.
Author contributions: The manuscript was written by N.A.A,
J.N and G.A.M. All authors have given approval to the final
version of the manuscript.
10.
Lee, K. L.; Ambler, C. M.; Anderson, D. R.; Boscoe,
Conflict of Interest: The authors are employees and
B. P.; Bree, A. G.; Brodfuehrer, J. I.; Chang, J. S.; Choi, C.;
Chung, S.; Curran, K. J.; Day, J. E.; Dehnhardt, C. M.; Dower,
K.; Drozda, S. E.; Frisbie, R. K.; Gavrin, L. K.; Goldberg, J.
A.; Han, S.; Hegen, M.; Hepworth, D.; Hope, H. R.;
Kamtekar, S.; Kilty, I. C.; Lee, A.; Lin, L. L.; Lovering, F.
E.; Lowe, M. D.; Mathias, J. P.; Morgan, H. M.; Murphy, E.
A.; Papaioannou, N.; Patny, A.; Pierce, B. S.; Rao, V. R.;
Saiah, E.; Samardjiev, I. J.; Samas, B. M.; Shen, M. W. H.;
Shin, J. H.; Soutter, H. H.; Strohbach, J. W.; Symanowicz, P.
T.; Thomason, J. R.; Trzupek, J. D.; Vargas, R.; Vincent, F.;
Yan, J.; Zapf, C. W.; Wright, S. W., Discovery of Clinical
Candidate 1-{[(2S,3S,4S)-3-Ethyl-4-fluoro-5-oxopyrrolidin-2-
yl]methoxy}-7-methoxyisoquinoli ne-6-carboxamide (PF-
06650833), a Potent, Selective Inhibitor of Interleukin-1
Receptor Associated Kinase 4 (IRAK4), by Fragment-Based
Drug Design. Journal of medicinal chemistry 2017, 60 (13),
5521-5542.
shareholders of GlaxoSmithKline.
Acknowledgments
We would like to thank Afjal Miah and Ian Smith for helpful
chemistry discussions, Jane Denyer and Zuni Bassi for biology
support, and Sebastien Campos and Andrew Benowitz for
reviewing the manuscript.
REFERENCES
1.
Nature reviews. Immunology 2004, 4 (7), 499-511.
2. Brzezinska, A. A.; Johnson, J. L.; Munafo, D. B.;
Akira, S.; Takeda, K., Toll-like receptor signalling.
Ellis, B. A.; Catz, S. D., Signalling mechanisms for Toll-like
receptor-activated neutrophil exocytosis: key roles for
interleukin-1-receptor-associated
phosphatidylinositol 3-kinase but not Toll/IL-1 receptor (TIR)
domain-containing adaptor inducing IFN-beta (TRIF).
Immunology 2009, 127 (3), 386-97.
kinase-4
and
11.
Sakamoto, K. M.; Kim, K. B.; Kumagai, A.;
Mercurio, F.; Crews, C. M.; Deshaies, R. J., Protacs: chimeric
molecules that target proteins to the Skp1-Cullin-F box
complex for ubiquitination and degradation. Proceedings of the
National Academy of Sciences of the United States of America
2001, 98 (15), 8554-9.
3.
O'Neill, L. A., The interleukin-1 receptor/Toll-like
receptor superfamily: 10 years of progress. Immunological
reviews 2008, 226, 10-8.
4.
Chiang, E. Y.; Yu, X.; Grogan, J. L., Immune
12.
Schneekloth, J. S., Jr.; Fonseca, F. N.; Koldobskiy,
complex-mediated cell activation from systemic lupus
erythematosus and rheumatoid arthritis patients elaborate
different requirements for IRAK1/4 kinase activity across
human cell types. Journal of immunology (Baltimore, Md. :
1950) 2011, 186 (2), 1279-88.
M.; Mandal, A.; Deshaies, R.; Sakamoto, K.; Crews, C. M.,
Chemical genetic control of protein levels: selective in vivo
targeted degradation. Journal of the American Chemical Society
2004, 126 (12), 3748-54.
13.
Bondeson, D. P.; Mares, A.; Smith, I. E.; Ko, E.;
5.
Ngo, V. N.; Young, R. M.; Schmitz, R.; Jhavar, S.;
Campos, S.; Miah, A. H.; Mulholland, K. E.; Routly, N.;
Buckley, D. L.; Gustafson, J. L.; Zinn, N.; Grandi, P.;
Xiao, W.; Lim, K. H.; Kohlhammer, H.; Xu, W.; Yang, Y.;
Zhao, H.; Shaffer, A. L.; Romesser, P.; Wright, G.; Powell,
J.; Rosenwald, A.; Muller-Hermelink, H. K.; Ott, G.;
Gascoyne, R. D.; Connors, J. M.; Rimsza, L. M.; Campo, E.;
Jaffe, E. S.; Delabie, J.; Smeland, E. B.; Fisher, R. I.; Braziel,
R. M.; Tubbs, R. R.; Cook, J. R.; Weisenburger, D. D.; Chan,
W. C.; Staudt, L. M., Oncogenically active MYD88 mutations
in human lymphoma. Nature 2011, 470 (7332), 115-9.
Shimamura, S.;
Bergamini, G.;
Faelth-Savitski, M.;
Bantscheff, M.; Cox, C.; Gordon, D. A.; Willard, R. R.;
Flanagan, J. J.; Casillas, L. N.; Votta, B. J.; den Besten, W.;
Famm, K.; Kruidenier, L.; Carter, P. S.; Harling, J. D.;
Churcher, I.; Crews, C. M., Catalytic in vivo protein
knockdown by small-molecule PROTACs. Nature chemical
biology 2015, 11 (8), 611-7.
ACS Paragon Plus Environment