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Crystallography of new drug class facilitates structure-based design

Department General

The Potter group, leading an international collaboration, has discovered newly-designed synthetic microtubule disruptors with excellent activities and desirable drug-like profiles. This first example of a new drug class bound to tubulin to be explored crystallographically opens up new avenues for structure-based anti-cancer drug design.

Structure of the new quinazolinone sulfamate – based drug candidate both alone (top) and co-crystallised with the αβ-tubulin dimer (bottom). Molecules are superimposed upon a background of HeLa cells expressing recombinant tagged tubulin visualised with a fluorescent dye (green), counterstained for DNA (blue) and imaged by confocal microscopy

This interdisciplinary and internationally collaborative discovery work describes newly designed synthetic anti-cancer drug candidates with development potential. The best quinazolinone sulfamate compound, derived from a concise structure-activity relationship using breast and prostate tumour cell lines, shows anti-proliferative activity in the 50 nM range, inhibits tubulin assembly and also interferes effectively with the colchicine binding site on tubulin. Importantly, it was also successfully co-crystallized with the αβ-tubulin heterodimer and found to bind more deeply in the colchicine binding site than colchicine itself at the dimer interface, with the key sulfamate group involved in the binding process through specific interactions with β-tubulin. Results suggest that the mechanism of microtubule destabilization is to prevent the curved-to-straight tubulin conformational transition. One compound was evaluated positively for in vivo activity in a mouse xenograft model of multiple myeloma, confirming the promise of this new synthetic template. This new crystallographic understanding of such sulfamate derivatives, in tandem with the highly favorable pharmaceutical properties afforded to such sulfamate esters and pioneered by the Potter group, should stimulate the structure-based design of other orally active colchicine site binding microtubule disruptors for anticancer drug development.

  •  Quinazolinone-based anticancer agents: Synthesis, antiproliferative SAR, anti-tubulin activity and tubulin co-crystal structure. W Dohle, F Jourdan, G  Menchon, A E Prota, P A Foster, P Mannion, E  Hamel, M P Thomas, P Kasprzyk,  E Ferrandis, M O Steinmetz, M P Leese and B V L Potter J Med Chem (2018) 61, 1031-1044. https://pubs.acs.org/doi/10.1021/acs.jmedchem.7b01474