Entomopathogenic fungi as microbial platforms for tyrosine kinase-oriented inhibitor discovery

Abstract Tyrosine kinase inhibitors (TKIs) remain a major focus of targeted therapeutic discovery, yet current discovery pipelines are constrained by resistance development, limited scaffold diversity, and high attrition rates. Entomopathogenic fungi (EPF) represent an underexplored microbial resource with significant biosynthetic potential for generating kinase-relevant secondary metabolites. Recent genomic studies reveal that EPF encode diverse and largely cryptic biosynthetic gene clusters (BGCs), including polyketide synthase (PKS), non-ribosomal peptide synthetase (NRPS), and hybrid pathways capable of producing structurally complex bioactive compounds. This mini-review examines the biotechnological exploitation of EPF for TKI discovery, focusing on fungal metabolites with direct or indirect kinase-related activity, genome mining strategies, biosynthetic logic, pathway regulation, and engineering approaches for metabolite production. Although only a limited number of EPF-derived metabolites have been experimentally validated as direct tyrosine kinase inhibitors, accumulating evidence indicates that many modulate kinase-associated signalling pathways and represent promising starting points for kinase-oriented natural product discovery. Particular emphasis is placed on pathway activation, heterologous expression, metabolic engineering, and scalable bioprocess development. Key translational challenges, including selectivity, toxicity, yield instability, and regulatory considerations, are also discussed. Collectively, this review highlights EPF as promising microbial platforms for kinase-oriented natural product discovery and provides a biotechnology-focused framework for advancing fungal secondary metabolites toward translational development. Key points • Entomopathogenic fungi encode diverse kinase-active secondary metabolites. • Genome mining and synthetic biology unlock cryptic TKI pathways. • Biotechnological optimization is critical for scalable fungal TKI discovery.