Cited by 55Statistical Methods in Clinical TrialsCancer Mechanisms and TherapyProtein Kinase Regulation and GTPase Signaling

Enzastaurin: A lesson in drug development

Bourhill, T., Narendran, A., Johnston, R.N.·2017·Critical Reviews in Oncology/Hematology

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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Crossref · 10.1016/j.critrevonc.2017.02.003

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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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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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