Enzastaurin: A lesson in drug development
Abstract
Enzastaurin is an orally administered drug that was intended for the treatment of solid and haematological cancers. It was initially developed as an isozyme specific inhibitor of protein kinase Cβ (PKCβ), which is involved in both the AKT and MAPK signalling pathways that are active in many cancers. Enzastaurin had shown encouraging preclinical results for the prevention of angiogenesis, inhibition of proliferation and induction of apoptosis as well as showing limited cytotoxicity within phase I clinical trials. However, during its assessment in phase II and III clinical trials the efficacy of enzastaurin was poor both in combination with other drugs and as a single agent. In this review, we will discuss the development of enzastaurin from drug design to clinical testing, exploring target identification, validation and preclinical assessment. Finally, we will consider the clinical evaluation of enzastaurin as an example of the challenges associated with drug development. In particular, we discuss the poor translation of drug efficacy from preclinical animal models, inappropriate end point analysis, limited standards in phase I clinical trials, insufficient use of biomarker analysis and also patient stratification, all of which contributed to the failure to achieve approval of enzastaurin as an anticancer therapeutic.
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Bryostatin 1 has recently entered phase II clinical trial against melanoma, non-Hodgkin's lymphoma, renal cancer and colorectal cancer.
“The bryostatin 1 has recently entered phase II clinical trial against melanoma, non-Hodgkin’s lymphoma, renal cancer and colorectal cancer [58,59,60].”
From Marine Natural Products: A Source of Novel Anticancer Drugs (2019) · cites this paper as [58]
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Flagged first, then by citations
3 of the 90 references couldn’t be matched to a known paper.
Cited by
Sorted by citations
Activators and Inhibitors of NRF2: A Review of Their Potential for Clinical Development
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Marine Natural Products: A Source of Novel Anticancer Drugs
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Lithium and Therapeutic Targeting of GSK-3
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Recent advances in the pathogenesis of microvascular complications in diabetes
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Equivocal, explicit and emergent actions of PKC isoforms in cancer
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LncRNA VEAL2 regulates PRKCB2 to modulate endothelial permeability in diabetic retinopathy
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A Systematic Review of Recently Reported Marine Derived Natural Product Kinase Inhibitors
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Cuadrado, A., Cazalla, E., Bach, A., Bathish, B., Naidu, S. D., DeNicola, G. M., Dinkova-Kostova, A. T., Fernández-Ginés, R., Grochot-Przeczek, A., Hayes, J. D., et al. (2025) · Redox Biology · doi:10.1016/j.redox.2025.103569 · Cited by 28 · see citing works
Perspectives on the Clinical Development of NRF2-Targeting Drugs
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A mitochondrial surveillance mechanism activated by SRSF2 mutations in hematologic malignancies
Liu, X., Devadiga, S. A., Stanley, R. F., Morrow, R. M., Janssen, K. A., Quesnel-Vallières, M., Pomp, O., Moverley, A. A., Li, C., Skuli, N., et al. (2024) · Journal of Clinical Investigation · doi:10.1172/jci175619 · Cited by 25 · see citing works
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Marine-Derived Bisindoles for Potent Selective Cancer Drug Discovery and Development
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Masnikosa, R., Cvetković, Z., & Pirić, D. (2024) · International Journal of Molecular Sciences · doi:10.3390/ijms252111384 · Cited by 21 · see citing works
Li, Y., Jiang, Y.-H., Hu, Z.-X., Yang, S., Li, L., Xiong, C., Gao, Y., Sun, W.-G., & Zhang, Y.-H. (2025) · MedComm · doi:10.1002/mco2.70474 · Cited by 23 · see citing works
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Emerging pharmaceutical therapies of Ascidian-derived natural products and derivatives
Cooreman, K., Spiegeleer, B. M. J. D., Poucke, C. V., Vanavermaete, D., Delbare, D., Wynendaele, E., & Witte, B. D. (2023) · Environmental Toxicology and Pharmacology · doi:10.1016/j.etap.2023.104254 · Cited by 16 · see citing works
Zavvarian, M.-M., Hong, J., Khazaei, M., Chio, J. C. T., Wang, J., Badner, A., & Fehlings, M. G. (2021) · Biomolecules · doi:10.3390/biom11070972 · Cited by 13 · see citing works
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Critical role of caveolin-1 in intestinal ischemia reperfusion by inhibiting protein kinase C βII
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BTK Inhibitors and Other Targeted Therapies in Waldenström Macroglobulinemia
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The PKC-β selective inhibitor, Enzastaurin, impairs memory in middle-aged rats
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Evaluation of current mouse in vivo models and advanced in vitro models for leukaemia research
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Enzastaurin enhances ATRA-induced differentiation of acute myeloid leukemia cells.
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Non-Pharmaceutical Interventions in Cancer Therapy
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The Sources, Structures and Cytotoxicity of Animal‐Derived Bisindole Compounds
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Modular Maleimide Synthesis from Ynamides
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Growth Factor Signaling Pathways and Targeted Therapy
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Enzasataurin Enhances ATRA-induced Differentiation of Acute Myeloid Leukemia CellsPreprint
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Protein kinase C in neurodegenerative disorders
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Synthesis of ACT-007 and Its Analogues with Antiproliferative Activity
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- Authors
- Bourhill, T., Narendran, A., & Johnston, R. N.
- Affiliations
- University of Calgary (CA)
- Corresponding author
- Bourhill, T.
- Venue
- Critical Reviews in Oncology/Hematology
- Publisher
- Elsevier BV
- Published
- 2017-04
- Volume
- 112
- Pages
- 72-79
- ISSN
- 1040-8428 (ISSN-L)
- OpenAlex
- W2586486297
- Cited by
- 55
- References
- 90
- Citations by year
- 2026: 7 · 2025: 9 · 2024: 7 · 2023: 6 · 2022: 2 · 2021: 5 · 2020: 7 · 2019: 9 · 2018: 3
- FWCI
- 0.96
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Critical Reviews in Oncology/Hematology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Canadian Breast Cancer Foundation
- Topics
- Physical Sciences › Mathematics › Statistics and Probability › Statistical Methods in Clinical Trials
- Health Sciences › Medicine › Pathology and Forensic Medicine › Cancer Mechanisms and Therapy
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Keywords
- enzastaurin, protein kinase C beta, drug development failure, anticancer agents, Akt signaling, MAPK signaling, angiogenesis inhibition, apoptosis, preclinical to clinical translation, clinical trial endpoints, biomarkers, patient stratification, drug repurposing
- MeSH terms
- Animals, Antineoplastic Agents, Humans, Indoles, Neoplasms, Drug Design, Protein Kinase C beta
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