Please cite this article in press as: Liu et al., Discovery of Small-Molecule Inhibitors of the HSP90-Calcineurin-NFAT Pathway against Glioblastoma, Cell
Fritz, L., Dirven, L., Reijneveld, J.C., Koekkoek, J.A., Stiggelbout, A.M.,
Pasman, H.R., and Taphoorn, M.J. (2016). Advance care planning in glioblas-
Monticelli, S., and Rao, A. (2002). NFAT1 and NFAT2 are positive regulators of
IL-4 gene transcription. Eur. J. Immunol. 32, 2971–2978.
€
Muller, M.R., and Rao, A. (2010). NFAT, immunity and cancer: a transcription
Gudlur, A., Zhou, Y., and Hogan, P.G. (2013). STIM-ORAI interactions that con-
factor comes of age. Nat. Rev. Immunol. 10, 645–656.
trol the CRAC channel. Curr. Top. Membr. 71, 33–58.
Nagata, S. (2018). Apoptosis and clearance of apoptotic cells. Annu. Rev.
Gutschner, T., Hammerle, M., and Diederichs, S. (2013). MALAT1 – a paradigm
Immunol. 36, 489–517.
for long noncoding RNA function in cancer. J. Mol. Med. 91, 791–801.
Nguyen, N.T., Han, W., Cao, W.M., Wang, Y., Wen, S., Huang, Y., Li, M., Du, L.,
and Zhou, Y. (2018). Store-operated calcium entry mediated by ORAI and
STIM. Compr. Physiol. 8, 981–1002.
Hogan, P.G., Lewis, R.S., and Rao, A. (2010). Molecular basis of calcium
signaling in lymphocytes: STIM and ORAI. Annu. Rev. Immunol. 28, 491–533.
Huang, W., Dong, Z., Chen, Y., Wang, F., Wang, C.J., Peng, H., He, Y.,
Hangoc, G., Pollok, K., Sandusky, G., et al. (2016). Small-molecule inhibitors
targeting the DNA-binding domain of STAT3 suppress tumor growth, metas-
tasis and STAT3 target gene expression in vivo. Oncogene 35, 783–792.
O’Duibhir, E., Carragher, N.O., and Pollard, S.M. (2017). Accelerating glioblas-
toma drug discovery: convergence of patient-derived models, genome editing
and phenotypic screening. Mol. Cell. Neurosci. 80, 198–207.
Pearson, J.R.D., and Regad, T. (2017). Targeting cellular pathways in glioblas-
Huang, Y., Zhou, Y., Wong, H.C., Chen, Y., Chen, Y., Wang, S., Castiblanco,
A., Liu, A., and Yang, J.J. (2009). A single EF-hand isolated from STIM1 forms
dimer in the absence and presence of Ca2+. FEBS J. 276, 5589–5597.
toma multiforme. Signal Transduct. Target. Ther. 2, 17040.
Prakriya, M., and Lewis, R.S. (2015). Store-operated calcium channels.
Physiol. Rev. 95, 1383–1436.
Iadevaia, S., Lu, Y., Morales, F.C., Mills, G.B., and Ram, P.T. (2010).
Identification of optimal drug combinations targeting cellular networks: inte-
grating phospho-proteomics and computational network analysis. Cancer
Res. 70, 6704–6714.
Preusser, M., Lim, M., Hafler, D.A., Reardon, D.A., and Sampson, J.H. (2015).
Prospects of immune checkpoint modulators in the treatment of glioblastoma.
Nat. Rev. Neurol. 11, 504–514.
Qin, J.J., Nag, S., Wang, W., Zhou, J., Zhang, W.D., Wang, H., and Zhang, R.
(2014). NFAT as cancer target: mission possible? Biochim. Biophys. Acta
1846, 297–311.
Jhaveri, K., Taldone, T., Modi, S., and Chiosis, G. (2012). Advances in the clin-
ical development of heat shock protein 90 (Hsp90) inhibitors in cancers.
Biochim. Biophys. Acta 1823, 742–755.
Rao, J.S. (2003). Molecular mechanisms of glioma invasiveness: the role of
Kastan, M.B., and Bartek, J. (2004). Cell-cycle checkpoints and cancer. Nature
proteases. Nat. Rev. Cancer 3, 489–501.
432, 316–323.
Kataoka, K., Shiraishi, Y., Takeda, Y., Sakata, S., Matsumoto, M., Nagano, S.,
Maeda, T., Nagata, Y., Kitanaka, A., Mizuno, S., et al. (2016). Aberrant PD-L1
expression through 3’-UTR disruption in multiple cancers. Nature 534,
402–406.
Roos, J., DiGregorio, P.J., Yeromin, A.V., Ohlsen, K., Lioudyno, M., Zhang, S.,
Safrina, O., Kozak, J.A., Wagner, S.L., Cahalan, M.D., et al. (2005). STIM1, an
essential and conserved component of store-operated Ca2+ channel function.
J. Cell Biol. 169, 435–445.
Khandelwal, A., Kent, C.N., Balch, M., Peng, S., Mishra, S.J., Deng, J., Day,
V.W., Liu, W., Subramanian, C., Cohen, M., et al. (2018). Structure-guided
design of an Hsp90beta N-terminal isoform-selective inhibitor. Nat. Commun.
9, 425.
Satelli, A., and Li, S. (2011). Vimentin in cancer and its potential as a molecular
target for cancer therapy. Cell. Mol. Life Sci. 68, 3033–3046.
Sauvageot, C.M., Weatherbee, J.L., Kesari, S., Winters, S.E., Barnes, J.,
Dellagatta, J., Ramakrishna, N.R., Stiles, C.D., Kung, A.L., Kieran, M.W.,
et al. (2009). Efficacy of the HSP90 inhibitor 17-AAG in human glioma cell lines
and tumorigenic glioma stem cells. Neuro Oncol. 11, 109–121.
Li, Z., Jia, L., Wang, J., Wu, X., Hao, H., Wu, Y., Xu, H., Wang, Z., Shi, G., Lu, C.,
et al. (2014). Discovery of diamine-linked 17-aroylamido-17-demethoxygelda-
namycins as potent Hsp90 inhibitors. Eur. J. Med. Chem. 87, 346–363.
Schopf, F.H., Biebl, M.M., and Buchner, J. (2017). The HSP90 chaperone ma-
´
Liberzon, A., Birger, C., Thorvaldsdottir, H., Ghandi, M., Mesirov, J.P., and
chinery. Nat. Rev. Mol. Cell Biol. 18, 345–360.
Tamayo, P. (2015). The molecular signatures database (MSigDB) hallmark
Schulke, J.P., McAllister, L.A., Geoghegan, K.F., Parikh, V., Chappie, T.A.,
Verhoest, P.R., Schmidt, C.J., Johnson, D.S., and Brandon, N.J. (2014).
Chemoproteomics demonstrates target engagement and exquisite selectivity
of the clinical phosphodiesterase 10A inhibitor MP-10 in its native environ-
ment. ACS Chem. Biol. 9, 2823–2832.
gene set collection. Cell Syst. 1, 417–425.
Liou, J., Kim, M.L., Heo, W.D., Jones, J.T., Myers, J.W., Ferrell, J.E., Jr., and
Meyer, T. (2005). STIM is a Ca2+ sensor essential for Ca2+-store-depletion-trig-
gered Ca2+ influx. Curr. Biol. 15, 1235–1241.
Liu, H., Tekle, C., Chen, Y.W., Kristian, A., Zhao, Y., Zhou, M., Liu, Z., Ding, Y.,
Wang, B., Maelandsmo, G.M., et al. (2011). B7-H3 silencing increases pacli-
taxel sensitivity by abrogating Jak2/Stat3 phosphorylation. Mol. Cancer
Ther. 10, 960–971.
Shinmen, N., Koshida, T., Kumazawa, T., Sato, K., Shimada, H., Matsutani, T.,
Iwadate, Y., Takiguchi, M., and Hiwasa, T. (2009). Activation of NFAT signal by
p53-K120R mutant. FEBS Lett. 583, 1916–1922.
Shrestha, L., Bolaender, A., Patel, H.J., and Taldone, T. (2016). Heat shock
protein (HSP) drug discovery and development: targeting heat shock proteins
in disease. Curr. Top. Med. Chem. 16, 2753–2764.
Mahalingam, D., Swords, R., Carew, J.S., Nawrocki, S.T., Bhalla, K., and Giles,
F.J. (2009). Targeting HSP90 for cancer therapy. Br. J. Cancer 100, 1523.
Mancini, M., and Toker, A. (2009). NFAT proteins: emerging roles in cancer
Sibbersen, C., Lykke, L., Gregersen, N., Jorgensen, K.A., and Johannsen, M.
(2014). A cleavable azide resin for direct click chemistry mediated enrichment
of alkyne-labeled proteins. Chem. Commun. 50, 12098–12100.
progression. Nat. Rev. Cancer 9, 810–820.
Martinez, G.J., Pereira, R.M., Aijo, T., Kim, E.Y., Marangoni, F., Pipkin, M.E.,
Togher, S., Heissmeyer, V., Zhang, Y.C., Crotty, S., et al. (2015). The transcrip-
tion factor NFAT promotes exhaustion of activated CD8(+) T cells. Immunity
42, 265–278.
Simpson, L., and Galanis, E. (2006). Recurrent glioblastoma multiforme: ad-
vances in treatment and promising drug candidates. Expert Rev. Anticancer
Ther. 6, 1593–1607.
Memmel, S., Sisario, D., Zoller, C., Fiedler, V., Katzer, A., Heiden, R., Becker,
N., Eing, L., Ferreira, F.L.R., Zimmermann, H., et al. (2017). Migration pattern,
actin cytoskeleton organization and response to PI3K-, mTOR-, and Hsp90-in-
hibition of glioblastoma cells with different invasive capacities. Oncotarget 8,
45298–45310.
Singh, S.D., Robbins, N., Zaas, A.K., Schell, W.A., Perfect, J.R., and Cowen,
L.E. (2009). Hsp90 governs echinocandin resistance in the pathogenic yeast
Candida albicans via calcineurin. PLoS Pathog. 5, e1000532.
Soboloff, J., Rothberg, B.S., Madesh, M., and Gill, D.L. (2012). STIM pro-
teins: dynamic calcium signal transducers. Nat. Rev. Mol. Cell Biol. 13,
549–565.
Mittal, S., Pradhan, S., and Srivastava, T. (2015). Recent advances in targeted
therapy for glioblastoma. Expert Rev. Neurother. 15, 935–946.
Monteiro, A.R., Hill, R., Pilkington, G.J., and Madureira, P.A. (2017). The
Su, T.T., Parry, D.H., Donahoe, B., Chien, C.T., O’Farrell, P.H., and Purdy, A.
(2001). Cell cycle roles for two 14-3-3 proteins during Drosophila development.
J. Cell Sci. 114, 3445–3454.
Cell Chemical Biology 26, 1–14, March 21, 2019 13