Executive Summary : | The natural product of tubulysin, which has shown promising biological activity, has been halted due to its scarcity and high cytotoxicity. To address this, researchers have synthesised several tubulysins and their anologues and antibody-drug conjugates (ADCs) for drug delivery. One of these analogues, tubulysin B folate antibody-drug conjugate EC1456 and EC1169, has been entered into clinical trials. However, these analogues still pose high complexity. To overcome this, researchers have designed two different molecules based on computational studies and FDA-approved boron-based drugs like bortezomib. The computational studies revealed that these designed ligands fit well into the binding pocket at the target compared to literature molecules. The new hydrogen bonds (Val353) were also observed by incorporating boronic acid. The newly proposed ligands have shown the highest docking score with glide, while compound F8.2 has shown -7.950. The successful synthesis of tubulysin-inspired boronic acid analogues and their anti-cancer activity investigation may lead to the identification of new potent tubulysin analogues for microtubule dynamic inhibitors. Additionally, researchers have designed macrocyclic analogues, which are more conformationally restricted than acyclic analogues due to their lower number of rotatable bonds. The simplification of length and rigidification of tubulysin natural products by making macrocycles while keeping intact the Tuv and Tup parts of natural tubulysins could create a new avenue in tubulysin chemistry towards anti-cancer drug discovery programs. |