The Different Faces of the Selective Human Telomerase Inhibitor: BIBR1532 and Its Derivatives

Telomerase is an interesting biological target for cancer treatment. Despite recent advances in telomerase research and the rapid development of new methodologies, significant challenges remain in identifying effective telomerase inhibitors with anticancer activity. In this manuscript, we provide computational studies to analyse how structural modification of BIBR1532, a selective and non-competitive telomerase inhibitor, may affect binding by a newly reported human telomerase model. BIBR1532 has been extensively studied in various cancer types, but analyses have shown its low anticancer activity. Further modification of BIBR1532 yielded compound BIBR1591 through a lipophilic morpholine ring extension of the benzoic acid. Interestingly, BIBR1591 showed approximately five-fold weaker inhibitory activity toward human telomerase relative to BIBR1532, but its in vivo preclinical studies have demonstrated significant anti-tumour and pro-apoptotic efficacy. Despite promising preclinical activities, neither compound has advanced to clinical trials, reportedly due to challenges with its pharmacokinetic properties. BIBR1532 suffers from poor solubility and low cellular uptake. This manuscript aims to provide an updated overview of human telomerase inhibition by BIBR1532 analogues and emphasise the importance of understanding its molecular mode of action based on the most updated literature. Using an in silico approach, we analysed how the structural modification of the BIBR scaffold influences the binding mode at the BIBR binding site recently discovered in the structure of human telomerase. We have also assessed whether reported analogues offer a measurable advantage over the parent compound.