Carbazole derivatives as privileged scaffolds for kinase inhibition: advances in design, therapeutic applications and mechanisms

Protein kinases are regarded as the most pursued drug targets in inflammatory diseases and oncology, and the carbazole scaffold has emerged as a versatile core for their inhibition owing to its planar, rigid tricyclic framework, which efficiently accommodates the kinase hinge region. This review consolidates the design and biological exploration of carbazole analogues and fused carbazole derivatives, including pyrrolocarbazole, indolocarbazoles, carbazole carboxamides, and various others, as inhibitors of several kinase families. These carbazole derivatives have been evaluated against VEGFR (Vascular Endothelial Growth Factor Receptor), EGFR (Epidermal Growth Factor Receptor), CDK (Cyclin-Dependent Kinase), PIM (Proviral Integration Site for Moloney Murine Leukemia Virus), MAPK (Mitogen-Activated Protein Kinase), BTK (Bruton’s Tyrosine Kinase), ALK (Anaplastic Lymphoma Kinase), JAK/STAT (Janus Kinase/Signal Transducer and Activator of Transcription signaling pathway), CHK (Checkpoint Kinase), and CK (Casein Kinase) protein kinases. Despite chemical versatility, these therapies remain constrained due to acquired resistance via non-gatekeeper and gatekeeper mutations, nonselective kinase inhibition, poor solubility, and metabolic vulnerability, collectively leading to poor oral bioavailability. Looking forward, structure-based carbazole derivative design for better ADME (absorption, distribution, metabolism, excretion) profile, allosteric and covalent inhibitor development are some of the gaps that need to be covered in future drug discovery.