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Isoquinoline-Based Biaryls as a Robust Scaffold for Microtubule Inhibitors

submitted on 06.08.2019, 09:55 and posted on 06.08.2019, 16:00 by Yvonne Kraus, Carina Glas, Benedikt Melzer, Li Gao, Constanze Heise, Monique Preusse, Julia Ahlfeld, Franz Bracher, Oliver Thorn-Seshold

We here report the discovery of isoquinoline-based biaryls as a new scaffold for colchicine domain tubulin inhibitors. Colchicine domain inhibitors comprise a structurally diverse class of compounds offering highly desirable cytotoxic and vascular disrupting bioactivities. Current research on colchicine domain inhibitors is focused on improving in vivo robustness and tolerability: properties that are inextricably linked to the scaffold structure employed. The isoquinoline-based biaryl scaffold we now report offers high-potency tubulin inhibition with excellent robustness and druglikeness, allowing solubility, in vivo tolerability and facile late-stage structural diversification through a tolerant synthetic route. We have confirmed the tubulin-binding properties and mechanism of these isoquinoline-based biaryls through a series of cellular tests and established safe in vivo dosing parameters in mice. By addressing several problems facing the current families of inhibitors, we thus expect that this new scaffold will find a range of powerful in vivo applications towards translational use in cancer therapy.


DFG SFB1032 Nanoagents for Spatiotemporal Control project B09

DFG SFB TRR152 project P24 number 239283807

DFG Emmy Noether TH2231/1-1


Email Address of Submitting Author


Ludwig-Maximilians University, Munich



ORCID For Submitting Author


Declaration of Conflict of Interest

no conflict of interest