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Current Topics in Medicinal Chemistry


ISSN (Print): 1568-0266
ISSN (Online): 1873-4294

Mini-Review Article

Preclinical and Clinical Studies on Bryostatins, A Class of Marine-Derived Protein Kinase C Modulators: A Mini-Review

Author(s): Rinky Raghuvanshi and Sandip B. Bharate *

Volume 20, Issue 12, 2020

Page: [1124 - 1135] Pages: 12

DOI: 10.2174/1568026620666200325110444

Price: $65


Bryostatins are complex macrolactones isolated from marine organisms Bryozoan Bugula neritina. They are potent modulators of protein kinase C isozymes (PKCα: ki = 1.3-188 nM), and are one of the most extensively investigated marine natural products in clinical trials. Although ~21 natural bryostatins have been isolated, however only bryostatin-1 (1) has received much interest among medicinal chemists and clinicians. The structure-activity relationship of bryostatins has been well established, with the identification of key pharmacophoric features important for PKC modulation. The low natural abundance and the long synthetic route have prompted medicinal chemists to come-up with simplified analogs. Bryostatin skeleton comprises three pyran rings connected to each other to form a macrocyclic lactone. The simplest analog 27 contains only one pyran, which is also able to modulate the PKCα activity; however, the cyclic framework appears to be essential for the desired level of potency. Another simplified analog 17 (“picolog”) exhibited potent and in-vivo efficacy against lymphoma. Bryostatin-1 (1) has shown an acceptable intravenous pharmacokinetic profile in mice and displayed promising in-vivo efficacy in mice models of various cancers and Alzheimer's disease. Bryostatin-1 was investigated in numerous Phase I/II oncology clinical trials; it has shown minimal effect as a single agent, however, provided encouraging results in combination with other chemotherapy agents. FDA has granted orphan drug status to bryostatin-1 in combination with paclitaxel for esophageal cancer. Bryostatin-1 has also received orphan drug status for fragile X syndrome. Bryostatin-1 was also investigated in clinical studies for Alzheimer's disease and HIV infection. In a nutshell, the natural as well as synthetic bryostatins have generated a strong hope to emerge as treatment for cancer along with many other diseases.

Keywords: Bryostatins, Bryostatin-1, Protein kinase C, Clinical trials, Cancer, Alzheimer's disease.

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Bharate, S.B.; Sawant, S.D.; Singh, P.P.; Vishwakarma, R.A. Kinase inhibitors of marine origin. Chem. Rev., 2013, 113(8), 6761-6815.
[] [PMID: 23679846]
Malve, H. Exploring the ocean for new drug developments: Marine pharmacology. J. Pharm. Bioallied Sci., 2016, 8(2), 83-91.
[] [PMID: 27134458]
Newman, D.J.; Cragg, G.M. Drugs and drug candidates from marine sources: an assessment of the current “State of Play”. Planta Med., 2016, 82(9-10), 775-789.
[] [PMID: 26891002]
Dall’Acqua, S. Natural products as antimitotic agents. Curr. Top. Med. Chem., 2014, 14(20), 2272-2285.
[] [PMID: 25434355]
Pettit, G.R.; Kamano, Y.; Herald, C.L. Antineoplastic agents, 118. Isolation and structure of bryostatin 9. J. Nat. Prod., 1986, 49(4), 661-664.
[] [PMID: 3783162]
Hale, K.J.; Manaviazar, S. New approaches to the total synthesis of the bryostatin antitumor macrolides. Chem. Asian J., 2010, 5(4), 704-754.
[] [PMID: 20354984]
Smith, J.B.; Smith, L.; Pettit, G.R. Bryostatins: potent, new mitogens that mimic phorbol ester tumor promoters. Biochem. Biophys. Res. Commun., 1985, 132(3), 939-945.
[] [PMID: 3907633]
Pettit, G.R.; Day, J.F.; Hartwell, J.L.; Wood, H.B. Antineoplastic components of marine animals. Nature, 1970, 227(5261), 962-963.
[] [PMID: 4393654]
Pettit, G.R.; Herald, C.L.; Doubek, D.L.; Herald, D.L.; Arnold, E.; Clardy, J. Isolation and structure of bryostatin 1. J. Am. Chem. Soc., 1982, 104, 6846-6848.
Hennings, H.; Blumberg, P.M.; Pettit, G.R.; Herald, C.L.; Shores, R.; Yuspa, S.H. Bryostatin 1, an activator of protein kinase C, inhibits tumor promotion by phorbol esters in SENCAR mouse skin. Carcinogenesis, 1987, 8(9), 1343-1346.
[] [PMID: 3621472]
Isakov, N.; Galron, D.; Mustelin, T.; Pettit, G.R.; Altman, A. Inhibition of phorbol ester-induced T cell proliferation by bryostatin is associated with rapid degradation of protein kinase C. J. Immunol., 1993, 150(4), 1195-1204.
[PMID: 8432975]
Wender, P.A.; Hinkle, K.W.; Koehler, M.F.; Lippa, B. The rational design of potential chemotherapeutic agents: synthesis of bryostatin analogues. Med. Res. Rev., 1999, 19(5), 388-407.
[<388:AID-MED6>3.0.CO;2-H] [PMID: 10502742]
Trenn, G.; Pettit, G.R.; Takayama, H.; Hu-Li, J.; Sitkovsky, M.V. Immunomodulating properties of a novel series of protein kinase C activators. The bryostatins. J. Immunol., 1988, 140(2), 433-439.
[PMID: 3257237]
Kortmansky, J.; Schwartz, G.K. Bryostatin-1: a novel PKC inhibitor in clinical development. Cancer Invest., 2003, 21(6), 924-936.
[] [PMID: 14735696]
Etcheberrigaray, R.; Alkon, D.L. Alkon, PCK activation as a means for enhancing aAPPa secretion and improving cognition using bryostatin type compounds US20110196028, WO2004004641. 2011.
Alkon, D.L. Methods for Alzheimer's disease treatment and cognitive enhancement. U.S. Patents US20110021508, US20080004332, WO2006031337, January 27th. 2011.
Alkon, D. Methods for Alzheimer's disease treatment and cognitive enhancement. US2010029744. 2010.
Etcheberrigaray, R.; Alkon, D.L. Alkon, Methods for Alzheimer's disease treatment and cognitive enhancement. WO2003075850. 2005.
Etcheberrigaray, R.; Tan, M.; Dewachter, I.; Kuipéri, C.; Van der Auwera, I.; Wera, S.; Qiao, L.; Bank, B.; Nelson, T.J.; Kozikowski, A.P.; Van Leuven, F.; Alkon, D.L. Therapeutic effects of PKC activators in Alzheimer’s disease transgenic mice. Proc. Natl. Acad. Sci. USA, 2004, 101(30), 11141-11146.
[] [PMID: 15263077]
Alkon, D.L.; Sun, M-K.; Nelson, T.J. PKC signaling deficits: a mechanistic hypothesis for the origins of Alzheimer’s disease. Trends Pharmacol. Sci., 2007, 28(2), 51-60.
[] [PMID: 17218018]
Way, K.J.; Katai, N.; King, G.L. Protein kinase C and the development of diabetic vascular complications. Diabet. Med., 2001, 18(12), 945-959.
[] [PMID: 11903393]
Yung-Hsiang, L.; Wing-Yee, C.; Yuan-Feng, L. Preparation of multipotent cells from monocytes. GB2468611. 2010.
Oba, M.; Kuroki, T. Method for reproducing hair. JP2006076967. 2006.
Castor, T. Combination therapy comprising the use of protein kinase C modulators and histone deacetylase inhibitors for treating HIV-1 latency. US2010166806. 2010.
Marsden, M.D.; Loy, B.A.; Wu, X.; Ramirez, C.M.; Schrier, A.J.; Murray, D.; Shimizu, A.; Ryckbosch, S.M.; Near, K.E.; Chun, T.W.; Wender, P.A.; Zack, J.A. activation of latent HIV with a synthetic bryostatin analog effects both latent cell “kick” and “kill” in strategy for virus eradication. PLoS Pathog., 2017, 13(9)e1006575
[] [PMID: 28934369]
Mohapatra, S.; Vergara, H. Protein kinase C as a target for the treatment of respiratory syncytial virus. US20090226423, US20080249057, US20040175384. 2009.
Zohar, O.; Alkon, D.L. Therapeutic effects of bryostatins, bryologs, and other related substances on head trauma-induced memory impairment and brain injury. WO2008143880. 2008.
Sun, M.-K.; Alkon, D.L. Therapeutic effects of Bryostatins, Bryologs, and other related substances on Ischemia/stroke-induced memory impairment and brain injury. WO2008100450. 2009.
Sun, M-K.; Hongpaisan, J.; Nelson, T.J.; Alkon, D.L. Poststroke neuronal rescue and synaptogenesis mediated by protein kinase C in adult brains. Proc. Natl. Acad. Sci. USA, 2008, 105(36), 13620-13625.
[] [PMID: 18768786]
Kornberg, M.D.; Smith, M.D.; Shirazi, H.A.; Calabresi, P.A.; Snyder, S.H.; Kim, P.M. Bryostatin-1 alleviates experimental multiple sclerosis. Proc. Natl. Acad. Sci. USA, 2018, 115(9), 2186-2191.
[] [PMID: 29440425]
Grant, S.; Roberts, J.; Poplin, E.; Tombes, M.B.; Kyle, B.; Welch, D.; Carr, M.; Bear, H.D. Phase Ib trial of bryostatin 1 in patients with refractory malignancies. Clin. Cancer Res., 1998, 4(3), 611-618.
[PMID: 9533528]
Zuo, L.; Li, J.; Ge, S.; Ge, Y.; Shen, M.; Wang, Y.; Zhou, C.; Wu, R.; Hu, J. Bryostatin-1 ameliorated experimental colitis in Il-10-/- Mice by protecting the intestinal barrier and limiting immune dysfunction. J. Cell. Mol. Med., 2019, 23(8), 5588-5599.
[] [PMID: 31251471]
Wender, P.A.; Hardman, C.T.; Ho, S.; Jeffreys, M.S.; Maclaren, J.K.; Quiroz, R.V.; Ryckbosch, S.M.; Shimizu, A.J.; Sloane, J.L.; Stevens, M.C. Scalable synthesis of bryostatin 1 and analogs, adjuvant leads against latent HIV. Science, 2017, 358(6360), 218-223.
[] [PMID: 29026042]
Castor, T.P. Bryoid compositions, methods of making and use thereof. EP2925315A4. 2013.
Keck, G.E.; Poudel, Y.B.; Cummins, T.J.; Rudra, A.; Covel, J.A. Total synthesis of bryostatin 1. J. Am. Chem. Soc., 2011, 133(4), 744-747.
[] [PMID: 21175177]
Kageyama, M.; Tamura, T.; Nantz, M.H.; Roberts, J.C.; Somfai, P.; Whritenour, D.C.; Masamune, S. Synthesis of bryostatin 7. J. Am. Chem. Soc., 1990, 112, 7407-7408.
Evans, D.A.; Carter, P.H.; Carreira, E.M.; Charette, A.B.; Prunet, J.A.; Lautens, M. Total synthesis of bryostatin 2. J. Am. Chem. Soc., 1999, 121, 7540-7552.
Ohmori, K.; Ogawa, Y.; Obitsu, T.; Ishikawa, Y.; Nishiyama, S.; Yamamura, S. Total Synthesis of Bryostatin 3 This work was supported by the Ministry of Education, Science, Sports, and Culture (Japan). K.O. is grateful to JSPS for a predoctoral fellowship. The authors thank Dr. G. N. Chmurny (NIH) for providing them with (1)H and (13)C NMR spectra of bryostatin 3 and for helpful discussions. Angew. Chem. Int. Ed. Engl., 2000, 39(13), 2290-2294.
[<2290:AID-ANIE2290>3.0.CO;2-6] [PMID: 10941067]
Trost, B.M.; Dong, G. Total synthesis of bryostatin 16 using atom-economical and chemoselective approaches. Nature, 2008, 456(7221), 485-488.
[] [PMID: 19037312]
Wender, P.A.; Schrier, A.J. Total synthesis of bryostatin 9. J. Am. Chem. Soc., 2011, 133(24), 9228-9231.
[] [PMID: 21618969]
Zhang, Y.; Guo, Q.; Sun, X.; Lu, J.; Cao, Y.; Pu, Q.; Chu, Z.; Gao, L.; Song, Z. Total synthesis of bryostatin 8 using an organosilane-based strategy. Angew. Chem. Int. Ed. Engl., 2018, 57(4), 942-946.
[] [PMID: 29210495]
Zhang, Y.; Lu, J.; Li, H.; Sun, X.; Gao, L.; Song, Z. Total synthesis of bryostatin 8 and (–)-exiguolide: applications of an organosilane strategy. Synlett, 2019, 30, 753-764.
Kollár, P.; Rajchard, J.; Balounová, Z.; Pazourek, J. Marine natural products: bryostatins in preclinical and clinical studies. Pharm. Biol., 2014, 52(2), 237-242.
[] [PMID: 24033119]
Irie, K.; Yanagita, R.C. Synthesis and biological activities of simplified analogs of the natural PKC ligands, bryostatin-1 and aplysiatoxin. Chem. Rec., 2014, 14(2), 251-267.
[] [PMID: 24677503]
Wu, R.; Chen, H.; Chang, N.; Xu, Y.; Jiao, J.; Zhang, H. Unlocking the drug potential of the bryostatin family: recent advances in product synthesis and biomedical applications. Chemistry, 2020, 26(6), 1166-1195.
[] [PMID: 31479550]
Azzi, A.; Boscoboinik, D.; Hensey, C. The protein kinase C family. Eur. J. Biochem., 1992, 208(3), 547-557.
[] [PMID: 1396661]
Cohen, P. Protein kinases--the major drug targets of the twenty-first century? Nat. Rev. Drug Discov., 2002, 1(4), 309-315.
[] [PMID: 12120282]
Castagna, M.; Takai, Y.; Kaibuchi, K.; Sano, K.; Kikkawa, U.; Nishizuka, Y. Direct activation of calcium-activated, phospholipid-dependent protein kinase by tumor-promoting phorbol esters. J. Biol. Chem., 1982, 257(13), 7847-7851.
[PMID: 7085651]
Isakov, N. Protein kinase C (PKC) isoforms in cancer, tumor promotion and tumor suppression. Semin. Cancer Biol., 2018, 48, 36-52.
[] [PMID: 28571764]
Luna-Ulloa, L.B.; Hernández-Maqueda, J.G.; Castañeda-Patlán, M.C.; Robles-Flores, M. Protein kinase C in Wnt signaling: implications in cancer initiation and progression. IUBMB Life, 2011, 63(10), 915-921.
[] [PMID: 21905203]
Bosco, R.; Melloni, E.; Celeghini, C.; Rimondi, E.; Vaccarezza, M.; Zauli, G. Fine tuning of protein kinase C (PKC) isoforms in cancer: shortening the distance from the laboratory to the bedside. Mini Rev. Med. Chem., 2011, 11(3), 185-199.
[] [PMID: 21534929]
Yu, H.B.; Yang, F.; Li, Y.Y.; Gan, J.H.; Jiao, W.H.; Lin, H.W. Cytotoxic bryostatin derivatives from the south china sea bryozoan bugula neritina. J. Nat. Prod., 2015, 78(5), 1169-1173.
[] [PMID: 25932671]
Hale, K.J.; Hummersone, M.G.; Manaviazar, S.; Frigerio, M. The chemistry and biology of the bryostatin antitumour macrolides. Nat. Prod. Rep., 2002, 19(4), 413-453.
[] [PMID: 12195811]
Ruan, B.F.; Zhu, H.L. The chemistry and biology of the bryostatins: potential PKC inhibitors in clinical development. Curr. Med. Chem., 2012, 19(16), 2652-2664.
[] [PMID: 22506770]
Szallasi, Z.; Smith, C.B.; Pettit, G.R.; Blumberg, P.M. Differential regulation of protein kinase C isozymes by bryostatin 1 and phorbol 12-myristate 13-acetate in NIH 3T3 fibroblasts. J. Biol. Chem., 1994, 269(3), 2118-2124.
[PMID: 8294465]
Hornung, R.L.; Pearson, J.W.; Beckwith, M.; Longo, D.L. Preclinical evaluation of bryostatin as an anticancer agent against several murine tumor cell lines: versus activity. Cancer Res., 1992, 52(1), 101-107.
[PMID: 1727368]
Weiyuan Xu, C.X.; Feng, Y. Bryostatin inhibits proliferation of ependymoma cells by suppressing expressions of cyclooxygenase-2 and interleukin-8. Trop. J. Pharm. Res., 2019, 18, 6.
Zeng, N.; Xu, Y.; Wu, Y.; Hongbo, T.; Wu, M. Bryostatin 1 causes attenuation of TPA‑mediated tumor promotion in mouse skin. Mol. Med. Rep., 2018, 17(1), 1077-1082.
[PMID: 29115558]
Wang, J.; Wang, Z.; Sun, Y.; Liu, D. Bryostatin-1 inhibits cell proliferation of hepatocarcinoma and induces cell cycle arrest by activation of GSK3β. Biochem. Biophys. Res. Commun., 2019, 512(3), 473-478.
[] [PMID: 30904158]
Pettit, G.R.; Gao, F.; Herald, D.L.; Blumberg, P.M.; Lewin, N.E.; Nieman, R.A. Antineoplastic agents. 224. Isolation and structure of neristatin 1. J. Am. Chem. Soc., 1991, 113, 6693-6695.
Pettit, G.R.; Sikovsky, M.V. Sikovsky, Bryostatins as immunomodulators ES2061963.
Kedei, N.; Lewin, N.E.; Géczy, T.; Selezneva, J.; Braun, D.C.; Chen, J.; Herrmann, M.A.; Heldman, M.R.; Lim, L.; Mannan, P.; Garfield, S.H.; Poudel, Y.B.; Cummins, T.J.; Rudra, A.; Blumberg, P.M.; Keck, G.E. Biological profile of the less lipophilic and synthetically more accessible bryostatin 7 closely resembles that of bryostatin 1. ACS Chem. Biol., 2013, 8(4), 767-777.
[] [PMID: 23369356]
Kedei, N.; Kraft, M.B.; Keck, G.E.; Herald, C.L.; Melody, N.; Pettit, G.R.; Blumberg, P.M. Neristatin 1 provides critical insight into bryostatin 1 structure-function relationships. J. Nat. Prod., 2015, 78(4), 896-900.
Wender, P.A.; Cribbs, C.M.; Koehler, K.F.; Sharkey, N.A.; Herald, C.L.; Kamano, Y.; Pettit, G.R.; Blumberg, P.M. Modeling of the bryostatins to the phorbol ester pharmacophore on protein kinase C. Proc. Natl. Acad. Sci. USA, 1988, 85(19), 7197-7201.
[] [PMID: 3174627]
Keck, G.E.; Li, W.; Kraft, M.B.; Kedei, N.; Lewin, N.E.; Blumberg, P.M. The bryostatin 1 A-ring acetate is not the critical determinant for antagonism of phorbol ester-induced biological responses. Org. Lett., 2009, 11(11), 2277-2280.
[] [PMID: 19419164]
Ueno, S.; Yanagita, R.C.; Murakami, K.; Murakami, A.; Tokuda, H.; Suzuki, N.; Fujiwara, T.; Irie, K. Identification and biological activities of bryostatins from Japanese bryozoan. Biosci. Biotechnol. Biochem., 2012, 76(5), 1041-1043.
[] [PMID: 22738985]
Wender, P.A.; DeBrabander, J.; Harran, P.G.; Jimenez, J.M.; Koehler, M.F.T.; Lippa, B.; Park, C.M.; Siedenbiedel, C.; Pettit, G.R. The design, computer modeling, solution structure, and biological evaluation of synthetic analogs of bryostatin 1. Proc. Natl. Acad. Sci. USA, 1998, 95(12), 6624-6629.
[] [PMID: 9618462]
Blumberg, P.M.; Szallasi, Z.; Pettit, G.R. Method of treating cancer using C-26 modified bryostatin. WO9734598, US6060505, AU9723379. 2000.
May, S.W.; Sensenbrenner, L.L. Stimulation of stem cell growth by bryostatins. WO1989005346. 1994.
Kedei, N.; Kraft, M.B.; Keck, G.E.; Herald, C.L.; Melody, N.; Pettit, G.R.; Blumberg, P.M. Neristatin 1 provides critical insight into bryostatin 1 structure-function relationships. J. Nat. Prod., 2015, 78(4), 896-900.
[] [PMID: 25808573]
Staveness, D.; Abdelnabi, R.; Near, K.E.; Nakagawa, Y.; Neyts, J.; Delang, L.; Leyssen, P.; Wender, P.A. Inhibition of chikungunya virus-induced cell death by salicylate-derived bryostatin analogues provides additional evidence for a pkc-independent pathway. J. Nat. Prod., 2016, 79(4), 680-684.
[] [PMID: 26900711]
Mears, P.R.; Hoekman, S.; Rye, C.E.; Bailey, F.P.; Byrne, D.P.; Eyers, P.A.; Thomas, E.J. Towards 20,20-difluorinated bryostatin: synthesis and biological evaluation of C17,C27-fragments. Org. Biomol. Chem., 2019, 17(6), 1487-1505.
[] [PMID: 30681118]
Cummins, T.J.; Kedei, N.; Czikora, A.; Lewin, N.E.; Kirk, S.; Petersen, M.E.; McGowan, K.M.; Chen, J.Q.; Luo, X.; Johnson, R.C.; Ravichandran, S.; Blumberg, P.M.; Keck, G.E. Synthesis and biological evaluation of fluorescent bryostatin analogues. ChemBioChem, 2018, 19(8), 877-889.
[] [PMID: 29424951]
Zhao, X.; Kedei, N.; Michalowski, A.; Lewin, N.E.; Keck, G.E.; Blumberg, P.M. Deletion of the c26 methyl substituent from the bryostatin analogue merle 23 has negligible impact on its biological profile and potency. ChemBioChem, 2018, 19(10), 1049-1059.
[] [PMID: 29517836]
Wender, P.A.; Debrabander, J.; Harran, P.G.; Jimenez, J.M.; Koehler, M.F.T.; Lippa, B.; Park, C.M.; Shiozaki, M. Synthesis of the first members of a new class of biologically active bryostatin analogues. J. Am. Chem. Soc., 1998, 120, 4534-4535.
Wender, P.A.; Horan, J.C.; Verma, V.A. Total synthesis and initial biological evaluation of new B-ring-modified bryostatin analogs. Org. Lett., 2006, 8(23), 5299-5302.
[] [PMID: 17078702]
Keck, G.E.; Kraft, M.B.; Truong, A.P.; Li, W.; Sanchez, C.C.; Kedei, N.; Lewin, N.E.; Blumberg, P.M. Convergent assembly of highly potent analogues of bryostatin 1 pyran annulation: bryostatin look-alikes that mimic phorbol ester function. J. Am. Chem. Soc., 2008, 130(21), 6660-6661.
[] [PMID: 18452293]
Stang, S.L.; Lopez-Campistrous, A.; Song, X.; Dower, N.A.; Blumberg, P.M.; Wender, P.A.; Stone, J.C. A proapoptotic signaling pathway involving RasGRP, Erk, and Bim in B cells. Exp. Hematol., 2009, 37(1), 122-134.
[] [PMID: 19100522]
Khan, T.K.; Nelson, T.J.; Verma, V.A.; Wender, P.A.; Alkon, D.L. A cellular model of Alzheimer’s disease therapeutic efficacy: PKC activation reverses Abeta-induced biomarker abnormality on cultured fibroblasts. Neurobiol. Dis., 2009, 34(2), 332-339.
[] [PMID: 19233276]
Wender, P.A.; Lippa, B. Synthesis and biological evaluation of bryostatin analogues: the role of the A-ring. Tetrahedron Lett., 2000, 41, 1007-1011.
Wender, P.A.H.K.W. Synthesis and biological evaluation of a new class of bryostatin analogues: the role of the C20 substituent in protein kinase C binding. Tetrahedron Lett., 2000, 41, 6725-6729.
Wender, P.A.; Baryza, J.L.; Bennett, C.E.; Bi, F.C.; Brenner, S.E.; Clarke, M.O.; Horan, J.C.; Kan, C.; Lacôte, E.; Lippa, B.; Nell, P.G.; Turner, T.M. The practical synthesis of a novel and highly potent analogue of bryostatin. J. Am. Chem. Soc., 2002, 124(46), 13648-13649.
[] [PMID: 12431074]
Keck, G.E.; Poudel, Y.B.; Rudra, A.; Stephens, J.C.; Kedei, N.; Lewin, N.E.; Peach, M.L.; Blumberg, P.M. Molecular modeling, total synthesis, and biological evaluations of C9-deoxy bryostatin 1. Angew. Chem. Int. Ed. Engl., 2010, 49(27), 4580-4584.
[] [PMID: 20491108]
Zhang, X.; Zhang, R.; Zhao, H.; Cai, H.; Gush, K.A.; Kerr, R.G.; Pettit, G.R.; Kraft, A.S. Preclinical pharmacology of the natural product anticancer agent bryostatin 1, an activator of protein kinase C. Cancer Res., 1996, 56(4), 802-808.
[PMID: 8631017]
Mohammad, R.M.; Varterasian, M.L.; Almatchy, V.P.; Hannoudi, G.N.; Pettit, G.R.; Al-Katib, A. Successful treatment of human chronic lymphocytic leukemia xenografts with combination biological agents auristatin PE and bryostatin 1. Clin. Cancer Res., 1998, 4(5), 1337-1343.
[PMID: 9607595]
DeChristopher, B.A.; Fan, A.C.; Felsher, D.W.; Wender, P.A. “Picolog,” a synthetically-available bryostatin analog, inhibits growth of MYC-induced lymphoma. Oncotarget, 2012, 3(1), 58-66.
[] [PMID: 22308267]
Boger, D. Bryostatin analog: improving on Nature’s design. Oncotarget, 2012, 3(2), 116-117.
[] [PMID: 22416072]
Hongpaisan, J.; Sun, M.K.; Alkon, D.L. PKC ε activation prevents synaptic loss, Aβ elevation, and cognitive deficits in Alzheimer’s disease transgenic mice. J. Neurosci., 2011, 31(2), 630-643.
[] [PMID: 21228172]
Nelson, T.J.; Sun, M.K.; Lim, C.; Sen, A.; Khan, T.; Chirila, F.V.; Alkon, D.L. Bryostatin effects on cognitive function and pkcε in alzheimer’s disease phase iia and expanded access trials. J. Alzheimers Dis., 2017, 58(2), 521-535.
[] [PMID: 28482641]
Schrott, L.M.; Jackson, K.; Yi, P.; Dietz, F.; Johnson, G.S.; Basting, T.F.; Purdum, G.; Tyler, T.; Rios, J.D.; Castor, T.P.; Alexander, J.S. Acute oral Bryostatin-1 administration improves learning deficits in the APP/PS1 transgenic mouse model of Alzheimer’s disease. Curr. Alzheimer Res., 2015, 12(1), 22-31.
[] [PMID: 25523423]
Sun, M.K.; Hongpaisan, J.; Lim, C.S.; Alkon, D.L. Bryostatin-1 restores hippocampal synapses and spatial learning and memory in adult fragile x mice. J. Pharmacol. Exp. Ther., 2014, 349(3), 393-401.
[] [PMID: 24659806]
Zhao, M.; Rudek, M.A.; He, P.; Smith, B.D.; Baker, S.D. Validation and implementation of a method for determination of bryostatin 1 in human plasma by using liquid chromatography/tandem mass spectrometry. Anal. Biochem., 2005, 337(1), 143-148.
[] [PMID: 15649387]
Clamp, A.R.; Blackhall, F.H.; Vasey, P.; Soukop, M.; Coleman, R.; Halbert, G.; Robson, L.; Jayson, G.C. Cancer Research UK Phase I/II Committee. A phase II trial of bryostatin-1 administered by weekly 24-hour infusion in recurrent epithelial ovarian carcinoma. Br. J. Cancer, 2003, 89(7), 1152-1154.
[] [PMID: 14520436]
Madhusudan, S.; Protheroe, A.; Propper, D.; Han, C.; Corrie, P.; Earl, H.; Hancock, B.; Vasey, P.; Turner, A.; Balkwill, F.; Hoare, S.; Harris, A.L. A multicentre phase II trial of bryostatin-1 in patients with advanced renal cancer. Br. J. Cancer, 2003, 89(8), 1418-1422.
[] [PMID: 14562010]
Haas, N.B.; Smith, M.; Lewis, N.; Littman, L.; Yeslow, G.; Joshi, I.D.; Murgo, A.; Bradley, J.; Gordon, R.; Wang, H.; Rogatko, A.; Hudes, G.R. Weekly bryostatin-1 in metastatic renal cell carcinoma: a phase II study. Clin. Cancer Res., 2003, 9(1), 109-114.
[PMID: 12538458]
Plimack, E.R.; Tan, T.; Wong, Y.N.; von Mehren, M.M.; Malizzia, L.; Roethke, S.K.; Litwin, S.; Li, T.; Hudes, G.R.; Haas, N.B. A phase I study of temsirolimus and bryostatin-1 in patients with metastatic renal cell carcinoma and soft tissue sarcoma. Oncologist, 2014, 19(4), 354-355.
[] [PMID: 24674872]
Lam, A.P.; Sparano, J.A.; Vinciguerra, V.; Ocean, A.J.; Christos, P.; Hochster, H.; Camacho, F.; Goel, S.; Mani, S.; Kaubisch, A. Phase II study of paclitaxel plus the protein kinase C inhibitor bryostatin-1 in advanced pancreatic carcinoma. Am. J. Clin. Oncol., 2010, 33(2), 121-124.
[PMID: 19738452]
Ku, G.Y.; Ilson, D.H.; Schwartz, L.H.; Capanu, M.; O’Reilly, E.; Shah, M.A.; Kelsen, D.P.; Schwartz, G.K. Phase II trial of sequential paclitaxel and 1 h infusion of bryostatin-1 in patients with advanced esophageal cancer. Cancer Chemother. Pharmacol., 2008, 62(5), 875-880.
[] [PMID: 18270704]
Winegarden, J.D.; Mauer, A.M.; Gajewski, T.F.; Hoffman, P.C.; Krauss, S.; Rudin, C.M.; Vokes, E.E. A phase II study of bryostatin-1 and paclitaxel in patients with advanced non-small cell lung cancer. Lung Cancer, 2003, 39(2), 191-196.
[] [PMID: 12581572]
Ajani, J.A.; Jiang, Y.; Faust, J.; Chang, B.B.; Ho, L.; Yao, J.C.; Rousey, S.; Dakhil, S.; Cherny, R.C.; Craig, C.; Bleyer, A. A multi-center phase II study of sequential paclitaxel and bryostatin-1 (NSC 339555) in patients with untreated, advanced gastric or gastroesophageal junction adenocarcinoma. Invest. New Drugs, 2006, 24(4), 353-357.
[] [PMID: 16683077]
Morgan, R.J., Jr; Leong, L.; Chow, W.; Gandara, D.; Frankel, P.; Garcia, A.; Lenz, H.J.; Doroshow, J.H. Phase II trial of bryostatin-1 in combination with cisplatin in patients with recurrent or persistent epithelial ovarian cancer: a California cancer consortium study. Invest. New Drugs, 2012, 30(2), 723-728.
[] [PMID: 20936324]
Pavlick, A.C.; Wu, J.; Roberts, J.; Rosenthal, M.A.; Hamilton, A.; Wadler, S.; Farrell, K.; Carr, M.; Fry, D.; Murgo, A.J.; Oratz, R.; Hochster, H.; Liebes, L.; Muggia, F. Phase I study of bryostatin 1, a protein kinase C modulator, preceding cisplatin in patients with refractory non-hematologic tumors. Cancer Chemother. Pharmacol., 2009, 64(4), 803-810.
[] [PMID: 19221754]
Nezhat, F.; Wadler, S.; Muggia, F.; Mandeli, J.; Goldberg, G.; Rahaman, J.; Runowicz, C.; Murgo, A.J.; Gardner, G.J. Phase II trial of the combination of bryostatin-1 and cisplatin in advanced or recurrent carcinoma of the cervix: a New York Gynecologic Oncology Group study. Gynecol. Oncol., 2004, 93(1), 144-148.
[] [PMID: 15047228]
Barr, P.M.; Lazarus, H.M.; Cooper, B.W.; Schluchter, M.D.; Panneerselvam, A.; Jacobberger, J.W.; Hsu, J.W.; Janakiraman, N.; Simic, A.; Dowlati, A.; Remick, S.C. Phase II study of bryostatin 1 and vincristine for aggressive non-Hodgkin lymphoma relapsing after an autologous stem cell transplant. Am. J. Hematol., 2009, 84(8), 484-487.
[] [PMID: 19536846]
Dowlati, A.; Lazarus, H.M.; Hartman, P.; Jacobberger, J.W.; Whitacre, C.; Gerson, S.L.; Ksenich, P.; Cooper, B.W.; Frisa, P.S.; Gottlieb, M.; Murgo, A.J.; Remick, S.C. Phase I and correlative study of combination bryostatin 1 and vincristine in relapsed B-cell malignancies. Clin. Cancer Res., 2003, 9(16 Pt 1), 5929-5935.
[PMID: 14676117]
Roberts, J.D.; Smith, M.R.; Feldman, E.J.; Cragg, L.; Millenson, M.M.; Roboz, G.J.; Honeycutt, C.; Thune, R.; Padavic-Shaller, K.; Carter, W.H.; Ramakrishnan, V.; Murgo, A.J.; Grant, S. Phase I study of bryostatin 1 and fludarabine in patients with chronic lymphocytic leukemia and indolent (non-Hodgkin’s) lymphoma. Clin. Cancer Res., 2006, 12(19), 5809-5816.
[] [PMID: 17020988]
El-Rayes, B.F.; Gadgeel, S.; Shields, A.F.; Manza, S.; Lorusso, P.; Philip, P.A. Phase I study of bryostatin 1 and gemcitabine. Clin. Cancer Res., 2006, 12(23), 7059-7062.
[] [PMID: 17145828]
Kortmansky, J.; Schwartz, G.K. Bryostatin-1: a novel PKC inhibitor in clinical development. Cancer Invest., 2003, 21(6), 924-936.
[] [PMID: 14735696]
Peterson, A.C.; Harlin, H.; Karrison, T.; Vogelzang, N.J.; Knost, J.A.; Kugler, J.W.; Lester, E.; Vokes, E.; Gajewski, T.F.; Stadler, W.M. University of Chicago Phase II Consortium. A randomized phase II trial of interleukin-2 in combination with four different doses of bryostatin-1 in patients with renal cell carcinoma. Invest. New Drugs, 2006, 24(2), 141-149.
[] [PMID: 16514482]
Farlow, M.R.; Thompson, R.E.; Wei, L.J.; Tuchman, A.J.; Grenier, E.; Crockford, D.; Wilke, S.; Benison, J.; Alkon, D.L.; Randomized, A.A. Randomized, double-blind, placebo-controlled, phase ii study assessing safety, tolerability, and efficacy of bryostatin in the treatment of moderately severe to severe alzheimer’s disease. J. Alzheimers Dis., 2019, 67(2), 555-570.
[] [PMID: 30530975]

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