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Current Molecular Pharmacology

Editor-in-Chief

ISSN (Print): 1874-4672
ISSN (Online): 1874-4702

Research Article

E7386 is not a Specific CBP/β-Catenin Antagonist

Author(s): Yusuke Higuchi, Cu Nguyen, Nyam-Osor Chimge, Ching Ouyang, Jia-Ling Teo and Michael Kahn*

Volume 17, 2024

Published on: 20 July, 2023

Article ID: e290523217409 Pages: 10

DOI: 10.2174/1874467217666230529114100

open_access

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Abstract

Background and Objective: The first clinically evaluated CBP/β-catenin antagonist, PRI-724, displayed an excellent safety profile administered intravenously via continuous infusion. Eisai recently disclosed a third-generation, orally available, reportedly CBP/β-catenin antagonist, E7386. However, several structural features and the reported cytotoxicity of E7386 were unexpected for a specific CBP/β-catenin antagonist. Therefore, we undertook a comparison of E7386 versus the highly specific bona fide CBP/β-catenin antagonists, ICG-001 and C82, the active agents derived from the prodrug PRI-724.

Introduction: CBP/β-catenin antagonists rebalance the equilibrium between CBP/β-catenin and p300/β-catenin dependent transcription and may be able to treat or prevent many diseases of aging via maintenance of somatic stem cell pool and regulating mitochondrial function and metabolism involved in differentiation and immune cell function. The safety, efficacy, and therapeutic potential of the specific CBP/β-catenin antagonists, ICG-001, and the second-generation compound, C82, the active agent derived from the pro-drug PRI-724, have been studied extensively in a variety of preclinical disease models and in the clinic for oncology and hepatic fibrosis. However, the lack of oral bioavailability has hampered the further development of PRI-724. Thus, Eisai recently proposed a third-generation, orally available, reportedly CBP/β-catenin antagonist E7386. Here, we have performed a comparative analysis of E7386 with the highly specific bona fide CBP/β-catenin antagonists, ICG-001 and C82.

Methods: We utilized a series of previously validated biochemical and transcriptional assays to investigate the selective targeting of the CBP/β-catenin interaction in conjunction with global transcriptional profiling to compare the three small molecules, ICG-001, C82, and E7386.

Result: Our data cast significant doubt that the mechanism of action of E7386 is via specific CBP/β-catenin antagonism.

Conclusion: It can thus be concluded that E7386 is not a specific CBP/β-catenin antagonist.

Keywords: CBP, β-catenin, ICG-001, C82, E7386, Antagonism.

[1]
Emami, K.H.; Nguyen, C.; Ma, H.; Kim, D.H.; Jeong, K.W.; Eguchi, M.; Moon, R.T.; Teo, J.L.; Kim, H.Y.; Moon, S.H.; Ha, J.R.; Kahn, M. A small molecule inhibitor of beta-catenin/CREB-binding protein transcription [corrected]. Proc. Natl. Acad. Sci., 2004, 101(34), 12682-12687.
[http://dx.doi.org/10.1073/pnas.0404875101] [PMID: 15314234]
[2]
McMillan, M.; Kahn, M. Investigating Wnt signaling: A chemogenomic safari. Drug Discov. Today, 2005, 10(21), 1467-1474.
[http://dx.doi.org/10.1016/S1359-6446(05)03613-5] [PMID: 16243267]
[3]
Kahn, M. Taking the road less traveled – the therapeutic potential of CBP/β-catenin antagonists. Expert Opin. Ther. Targets, 2021, 25(9), 701-719.
[http://dx.doi.org/10.1080/14728222.2021.1992386] [PMID: 34633266]
[4]
Thomas, P.D.; Kahn, M. Kat3 coactivators in somatic stem cells and cancer stem cells: Biological roles, evolution, and pharmacologic manipulation. Cell Biol. Toxicol., 2016, 32(1), 61-81.
[http://dx.doi.org/10.1007/s10565-016-9318-0] [PMID: 27008332]
[5]
Hu, X.; Ono, M.; Chimge, N.O.; Chosa, K.; Nguyen, C.; Melendez, E.; Lou, C.H.; Lim, P.; Termini, J.; Lai, K.K.Y.; Fueger, P.T.; Teo, J.L.; Higuchi, Y.; Kahn, M. Differential Kat3 usage orchestrates the integration of cellular metabolism with differentiation. Cancers, 2021, 13(23), 5884.
[http://dx.doi.org/10.3390/cancers13235884] [PMID: 34884992]
[6]
Rieger, M.E.; Zhou, B.; Solomon, N.; Sunohara, M.; Li, C.; Nguyen, C.; Liu, Y.; Pan, J.; Minoo, P.; Crandall, E.D.; Brody, S.L.; Kahn, M.; Borok, Z. p300/β-catenin interactions regulate adult progenitor cell differentiation downstream of WNT5a/protein kinase C (PKC). J. Biol. Chem., 2016, 291(12), 6569-6582.
[http://dx.doi.org/10.1074/jbc.M115.706416] [PMID: 26833564]
[7]
Zhao, Y.; Masiello, D.; McMillian, M.; Nguyen, C.; Wu, Y.; Melendez, E.; Smbatyan, G.; Kida, A.; He, Y.; Teo, J-L.; Kahn, M. CBP/catenin antagonist safely eliminates drug-resistant leukemia-initiating cells. Oncogene, 2016, 35(28), 3705-3717.
[http://dx.doi.org/10.1038/onc.2015.438] [PMID: 26657156]
[8]
Miyabayashi, T.; Teo, J.L.; Yamamoto, M.; McMillan, M.; Nguyen, C.; Kahn, M. Wnt/β-catenin/CBP signaling maintains long-term murine embryonic stem cell pluripotency. Proc. Natl. Acad. Sci., 2007, 104(13), 5668-5673.
[http://dx.doi.org/10.1073/pnas.0701331104] [PMID: 17372190]
[9]
Teo, J.L.; Ma, H.; Nguyen, C.; Lam, C.; Kahn, M. Specific inhibition of CBP/β-catenin interaction rescues defects in neuronal differentiation caused by a presenilin-1 mutation. Proc. Natl. Acad. Sci., 2005, 102(34), 12171-12176.
[http://dx.doi.org/10.1073/pnas.0504600102] [PMID: 16093313]
[10]
Higuchi, Y.; Nguyen, C.; Yasuda, S.Y.; McMillan, M.; Hasegawa, K.; Kahn, M. Specific direct small molecule p300/β-catenin antagonists maintain stem cell potency. Curr. Mol. Pharmacol., 2016, 9(3), 272-279.
[http://dx.doi.org/10.2174/1874467208666150526155146] [PMID: 26008738]
[11]
Ma, H.; Nguyen, C.; Lee, K.S.; Kahn, M. Differential roles for the coactivators CBP and p300 on TCF/β-catenin-mediated survivin gene expression. Oncogene, 2005, 24(22), 3619-3631.
[http://dx.doi.org/10.1038/sj.onc.1208433] [PMID: 15782138]
[12]
Kumar, S.R.; Scehnet, J.S.; Ley, E.J.; Singh, J.; Krasnoperov, V.; Liu, R.; Manchanda, P.K.; Ladner, R.D.; Hawes, D.; Weaver, F.A.; Beart, R.W.; Singh, G.; Nguyen, C.; Kahn, M.; Gill, P.S. Preferential induction of EphB4 over EphB2 and its implication in colorectal cancer progression. Cancer Res., 2009, 69(9), 3736-3745.
[http://dx.doi.org/10.1158/0008-5472.CAN-08-3232] [PMID: 19366806]
[13]
El-Khoueiry, A.B.; Ning, Y.; Yang, D.; Cole, S.; Kahn, M.; Zoghbi, M.; Berg, J.; Fujimori, M.; Inada, T.; Kouji, H.; Lenz, H-J. A phase I first-in-human study of PRI-724 in patients (pts) with advanced solid tumors. J. Clin. Oncol., 2013, 31(S15), 2501.
[http://dx.doi.org/10.1200/jco.2013.31.15_suppl.2501]
[14]
Yamada, K.; Hori, Y.; Yamaguchi, A.; Matsuki, M.; Tsukamoto, S.; Yokoi, A. E7386: First-in-class orally active CBP/beta-catenin modulator as an anticancer agent. Cancer Res., 2017, 77(S13)
[15]
Yamada, K.; Hori, Y.; Inoue, S.; Yamamoto, Y.; Iso, K.; Kamiyama, H.; Yamaguchi, A.; Kimura, T.; Uesugi, M.; Ito, J.; Matsuki, M.; Nakamoto, K.; Harada, H.; Yoneda, N.; Takemura, A.; Kushida, I.; Wakayama, N.; Kubara, K.; Kato, Y.; Semba, T.; Yokoi, A.; Matsukura, M.; Odagami, T.; Iwata, M.; Tsuruoka, A.; Uenaka, T.; Matsui, J.; Matsushima, T.; Nomoto, K.; Kouji, H.; Owa, T.; Funahashi, Y.; Ozawa, Y. E7386, a selective inhibitor of the interaction between β-catenin and CBP, exerts antitumor activity in tumor models with activated canonical wnt signaling. Cancer Res., 2021, 81(4), 1052-1062.
[http://dx.doi.org/10.1158/0008-5472.CAN-20-0782] [PMID: 33408116]
[16]
Kanda, Y.; Ohata, H.; Miyazaki, T.; Sakai, H.; Mori, Y.; Shiokawa, D.; Yokoi, A.; Owa, T.; Ochiai, A.; Okamoto, K. NF-κB suppression synergizes with E7386, an inhibitor of CBP/β-catenin interaction, to block proliferation of patient-derived colon cancer spheroids. Biochem. Biophys. Res. Commun., 2022, 586, 93-99.
[http://dx.doi.org/10.1016/j.bbrc.2021.11.063] [PMID: 34837838]
[17]
Imai, T.; Naruse, M.; Ochiai, M.; Matsumoto, K.; Ikeda, S.; Kani, M.; Kato, Y.; Hirayama, A.; Soga, T.; Hori, Y.; Yokoi, A.; Ochiai, A. Different types of reactions to E7386 among colorectal cancer patient-derived organoids and corresponding CAFs. Oncol. Lett., 2022, 24(1), 221.
[http://dx.doi.org/10.3892/ol.2022.13342] [PMID: 35707761]
[18]
Mouradov, D.; Sloggett, C.; Jorissen, R.N.; Love, C.G.; Li, S.; Burgess, A.W.; Arango, D.; Strausberg, R.L.; Buchanan, D.; Wormald, S.; O’Connor, L.; Wilding, J.L.; Bicknell, D.; Tomlinson, I.P.M.; Bodmer, W.F.; Mariadason, J.M.; Sieber, O.M. Colorectal cancer cell lines are representative models of the main molecular subtypes of primary cancer. Cancer Res., 2014, 74(12), 3238-3247.
[http://dx.doi.org/10.1158/0008-5472.CAN-14-0013] [PMID: 24755471]
[19]
Chen, Y.; Huang, B.; Zhao, Y.; Qi, D.; Wang, D. Increased p300/CBP expression in acute respiratory distress syndrome is associated with interleukin-17 and prognosis. Clin. Respir. J., 2020, 14(9), crj.13197.
[http://dx.doi.org/10.1111/crj.13197] [PMID: 32298537]
[20]
Hammitzsch, A.; Tallant, C.; Fedorov, O.; O’Mahony, A.; Brennan, P.E.; Hay, D.A.; Martinez, F.O.; Al-Mossawi, M.H.; de Wit, J.; Vecellio, M.; Wells, C.; Wordsworth, P.; Müller, S.; Knapp, S.; Bowness, P. CBP30, a selective CBP/p300 bromodomain inhibitor, suppresses human Th17 responses. Proc. Natl. Acad. Sci., 2015, 112(34), 10768-10773.
[http://dx.doi.org/10.1073/pnas.1501956112] [PMID: 26261308]
[21]
Li, T.Y.; Sleiman, M.B.; Li, H.; Gao, A.W.; Mottis, A.; Bachmann, A.M.; Alam, G.E.; Li, X.; Goeminne, L.J.E.; Schoonjans, K.; Auwerx, J. The transcriptional coactivator CBP/p300 is an evolutionarily conserved node that promotes longevity in response to mitochondrial stress. Nature Aging, 2021, 1(2), 165-178.
[http://dx.doi.org/10.1038/s43587-020-00025-z] [PMID: 33718883]
[22]
Lill, N.L.; Grossman, S.R.; Ginsberg, D.; DeCaprio, J.; Livingston, D.M. Binding and modulation of p53 by p300/CBP coactivators. Nature, 1997, 387(6635), 823-827.
[http://dx.doi.org/10.1038/42981] [PMID: 9194565]
[23]
Grossman, S.R. p300/CBP/p53 interaction and regulation of the p53 response. Eur. J. Biochem., 2001, 268(10), 2773-2778.
[http://dx.doi.org/10.1046/j.1432-1327.2001.02226.x] [PMID: 11358491]
[24]
Sen, P.; Lan, Y.; Li, C.Y.; Sidoli, S.; Donahue, G.; Dou, Z.; Frederick, B.; Chen, Q.; Luense, L.J.; Garcia, B.A.; Dang, W.; Johnson, F.B.; Adams, P.D.; Schultz, D.C.; Berger, S.L. Histone Acetyltransferase p300 Induces De Novo Super-Enhancers to Drive Cellular Senescence. Mol. Cell, 2019, 73(4), 684-698.e8.
[http://dx.doi.org/10.1016/j.molcel.2019.01.021] [PMID: 30773298]
[25]
Li, Y.; Zhong, H.; Wu, M.; Tan, B.; Zhao, L.; Yi, Q.; Xu, X.; Pan, H.; Bi, Y.; Yang, K. Decline of p300 contributes to cell senescence and growth inhibition of hUC-MSCs through p53/p21 signaling pathway. Biochem. Biophys. Res. Commun., 2019, 515(1), 24-30.
[http://dx.doi.org/10.1016/j.bbrc.2019.05.061] [PMID: 31122700]
[26]
Di Giorgio, E.; Paluvai, H.; Dalla, E.; Ranzino, L.; Renzini, A.; Moresi, V.; Minisini, M.; Picco, R.; Brancolini, C. HDAC4 degradation during senescence unleashes an epigenetic program driven by AP-1/p300 at selected enhancers and super-enhancers. Genome Biol., 2021, 22(1), 129.
[http://dx.doi.org/10.1186/s13059-021-02340-z] [PMID: 33966634]
[27]
Yang, K.; Wang, F.; Zhang, H.; Wang, X.; Chen, L.; Su, X.; Wu, X.; Han, Q.; Chen, Z.; Chen, Z.S.; Fu, L. Target inhibition of CBP induced cell senescence in BCR-ABL- T315I mutant chronic myeloid leukemia. Front. Oncol., 2021, 10, 588641.
[http://dx.doi.org/10.3389/fonc.2020.588641] [PMID: 33585207]
[28]
Pei, Y.; Qian, Y.; Wang, H.; Tan, L. Epigenetic regulation of ferroptosis-associated genes and its implication in cancer therapy. Front. Oncol., 2022, 12, 771870.
[http://dx.doi.org/10.3389/fonc.2022.771870] [PMID: 35174081]
[29]
Wortel, I.M.N.; van der Meer, L.T.; Kilberg, M.S.; van Leeuwen, F.N. Surviving stress: Modulation of ATF4-mediated stress responses in normal and malignant cells. Trends Endocrinol. Metab., 2017, 28(11), 794-806.
[http://dx.doi.org/10.1016/j.tem.2017.07.003] [PMID: 28797581]
[30]
Gombart, A.F.; Grewal, J.; Koeffler, H.P. ATF4 differentially regulates transcriptional activation of myeloid-specific genes by C/EBPε and C/EBPα. J. Leukoc. Biol., 2007, 81(6), 1535-1547.
[http://dx.doi.org/10.1189/jlb.0806516] [PMID: 17347301]
[31]
Yukawa, K.; Tanaka, T.; Tsuji, S.; Akira, S. Regulation of transcription factor C/ATF by the cAMP signal activation in hippocampal neurons, and molecular interaction of C/ATF with signal integrator CBP/p300. Brain Res. Mol. Brain Res., 1999, 69(1), 124-134.
[http://dx.doi.org/10.1016/S0169-328X(99)00086-8] [PMID: 10350644]
[32]
Liang, G.; Hai, T. Characterization of human activating transcription factor 4, a transcriptional activator that interacts with multiple domains of cAMP-responsive element-binding protein (CREB)-binding protein. J. Biol. Chem., 1997, 272(38), 24088-24095.
[http://dx.doi.org/10.1074/jbc.272.38.24088] [PMID: 9295363]
[33]
Lassot, I.; Estrabaud, E.; Emiliani, S.; Benkirane, M.; Benarous, R.; Margottin-Goguet, F. p300 modulates ATF4 stability and transcriptional activity independently of its acetyltransferase domain. J. Biol. Chem., 2005, 280(50), 41537-41545.
[http://dx.doi.org/10.1074/jbc.M505294200] [PMID: 16219772]
[34]
Liu, Y.; Dentin, R.; Chen, D.; Hedrick, S.; Ravnskjaer, K.; Schenk, S.; Milne, J.; Meyers, D.J.; Cole, P.; Iii, J.Y.; Olefsky, J.; Guarente, L.; Montminy, M. A fasting inducible switch modulates gluconeogenesis via activator/coactivator exchange. Nature, 2008, 456(7219), 269-273.
[http://dx.doi.org/10.1038/nature07349] [PMID: 18849969]
[35]
Inaba, M.; Yamashita, Y.M. Asymmetric stem cell division: precision for robustness. Cell Stem Cell, 2012, 11(4), 461-469.
[http://dx.doi.org/10.1016/j.stem.2012.09.003] [PMID: 23040475]
[36]
Venkei, Z.G.; Yamashita, Y.M. Emerging mechanisms of asymmetric stem cell division. J. Cell Biol., 2018, 217(11), 3785-3795.
[http://dx.doi.org/10.1083/jcb.201807037] [PMID: 30232100]
[37]
Kimura, K.; Ikoma, A.; Shibakawa, M.; Shimoda, S.; Harada, K.; Saio, M.; Imamura, J.; Osawa, Y.; Kimura, M.; Nishikawa, K.; Okusaka, T.; Morita, S.; Inoue, K.; Kanto, T.; Todaka, K.; Nakanishi, Y.; Kohara, M.; Mizokami, M. Safety, tolerability, and preliminary efficacy of the anti-fibrotic small molecule PRI-724, a CBP/β-catenin inhibitor, in patients with hepatitis C virus-related cirrhosis: A single-center, open-label, dose escalation phase 1 trial. EBioMedicine, 2017, 23, 79-87.
[http://dx.doi.org/10.1016/j.ebiom.2017.08.016] [PMID: 28844410]
[38]
Kimura, K.; Kanto, T.; Shimoda, S.; Harada, K.; Kimura, M.; Nishikawa, K.; Imamura, J.; Ogawa, E.; Saio, M.; Ikura, Y.; Okusaka, T.; Inoue, K.; Ishikawa, T.; Ieiri, I.; Kishimoto, J.; Todaka, K.; Kamisawa, T. Safety, tolerability, and anti-fibrotic efficacy of the CBP/β-catenin inhibitor PRI-724 in patients with hepatitis C and B virus-induced liver cirrhosis: An investigator-initiated, open-label, non-randomised, multicentre, phase 1/2a study. EBioMedicine, 2022, 80, 104069.
[http://dx.doi.org/10.1016/j.ebiom.2022.104069] [PMID: 35605429]

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