The Groebke–Blackburn–Bienaymé (GBB) Reaction: A Powerful Tool for Generating Diverse Heterocyclic Scaffold Libraries in Anticancer Drug Discovery

Abstract

The Groebke–Blackburn–Bienaymé (GBB) reaction is a versatile multi-component (MCR) synthetic methodology that has transformed anticancer drug discovery by enabling the rapid and efficient generation of diverse heterocyclic scaffolds. These scaffolds, such as imidazo[1,2-a]pyridines, imidazo[1,2-a]pyrimidines, and their derivatives, are highly valuable moieties for targeting critical cancer pathways. The modular nature of the GBB reaction, coupled with post-reaction modifications, allows the design of compounds with tailored structures and enhanced pharmacological properties. GBB-derived compounds exhibit broad anticancer potential by modulating diverse molecular targets. These include protein kinases (e.g. Rock2, Gsk3β, B-Raf), microtubule dynamics via tubulin inhibition, and G-quadruplex DNA stabilization in oncogene promoters (e.g., c-MYC, BCL2), disrupting key mechanisms of tumour progression. Moreover, they target epigenetic regulators such as HDACs, CBP/P300 bromodomains, and BET bromodomains, affecting transcriptional regulation and chromatin remodeling. Immune checkpoints (e.g., PD-1/PD-L1), enzymes such as autotaxin, TDP1, and Hsp90, as well as apoptotic regulators (e.g., Bcl-2, BAG3), are also effectively inhibited. More importantly, these compounds address challenging targets, including KRAS G12C mutations and the menin–MLL interaction, offering solutions to previously "undruggable" pathways. The unparalleled efficiency of GBB reaction and its ability to generate structurally diverse, bioactive compounds spanning multiple oncogenic mechanisms highlights its central role in advancing anticancer drug discovery and its transformative impact on therapeutic innovation.