Design and synthesis of bromodomain and extra-terminal domain (BET) inhibitors
Publication Date
July 31, 2026
Creator
Zaidi, Jaffer
Abstract
Bromodomain and extra-terminal domain (BET) proteins, particularly bromodomain-containing protein 4 (BRD4), are epigenetic readers that regulate transcription of key oncogenes such as cellular myelocytomatosis (c-Myc). Consequently, targeted BET inhibition represents a validated therapeutic strategy in oncology. This thesis describes the development of novel small molecule BET inhibitors, integrating classical medicinal chemistry with machine learning (ML)-guided molecular design to explore new chemical space while maintaining synthetic tractability. Three inhibitor series were investigated. A triazinoindole scaffold incorporating a dimethylisoxazole N-acetylated lysine mimetic was designed to target the first bromodomain (BD1) of BRD4, enabling systematic structure-activity relationship studies and identification of compounds with nanomolar biochemical potency and favourable lipophilic efficiency (LipE). Two additional series, based on indole and benzimidazolone scaffolds, were prioritised for synthesis using a Python-based molecular generator (PyMolGen) and an ML 2D-QSAR model. While in some cases this approach improved physicochemical properties, in general biological activities proved modest and within a narrow micromolar range. Overall, this work establishes novel, synthetically accessible BET inhibitor scaffolds and demonstrates the practical integration of ML into medicinal chemistry decision-making.
Item Type
ethesis
Thesis Type
PhD
Supervisors
Subjects (LC)
Associated Schools / Departments
School of Pharmacy (UK)
eprints ID
83038
UoN Repository URI
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Name
Jaffer Zaidi PhD Thesis (Corrected).pdf
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Full-text
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Format
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