Ponatinib analogues: Virtual screening, precursor, synthesis, and approaches in the preparation of selected compounds

• Main Author: Padilla, Vince Lambert H.
• Format: text
• Language: English
• Published: Animo Repository 2020
• Subjects: Myeloid leukemia > Treatment; Chemistry
• Online Access: https://animorepository.dlsu.edu.ph/etd_masteral/6337; https://animorepository.dlsu.edu.ph/cgi/viewcontent.cgi?article=13407&context=etd_masteral
• Institution: De La Salle University

Ponatinib (AP24534), a chemotherapeutic agent used to treat chronic myeloid leukemia, exhibits its action through the competitive inhibition of BCR-ABL tyrosine kinases. Although it is potent enough to inhibit resistant variants of the enzyme including the T315I mutant, compound point mutations in the Philadelphia chromosome led to the formation of ponatinib-resistant kinases. In this study, 400 nucleobase-containing analogues were designed and were virtually screened through molecular docking simulations and ADME prediction tools. In reference to the affinity scores of ponatinib towards the target models (1.000WT; 0.994T3151), 92 analogues exhibited good scores in the wild type model, 69 in the T3151 model, while only 33 have scores higher than ponatinib in both models. Of the 33 top analogues, 24 have passed the ADME screens where 15 have predicted properties that are better than ponatinib. Based on the screening results, two synthetic approaches for the preparation of VP10101 (4a; 1.119WT; 1.010T3151), and VP30101a (8b; 1.004WT; 0.681T3151) were tested. Six precursors, three of which are new compounds, were successfully synthesized through amide coupling, Sonogashira coupling, and silver-catalyzed bromination reactions, with yields ranging from fair to qualitative (~50 to ~100%). The copper-catalyzed approach in the coupling of bromoalkynes with the mucleobases adenine and cytosine however did not proceed.