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Design, Synthesis, and Characterization of Brequinar Conjugates as Probes to Study DHODH Inhibition

2017; Wiley; Volume: 23; Issue: 56 Linguagem: Inglês

10.1002/chem.201702999

1521-3765

Joseph T. Madak, Christine R. Cuthbertson, Wen‐Ming Chen, Hollis D. Showalter, Nouri Neamati,

Ubiquitin and proteasome pathways

Brequinar, a potent dihydroorotate dehydrogenase (DHODH) inhibitor, has been evaluated in multiple clinical trials as a potential treatment for cancer. To further understand brequinar-based DHODH inhibition and DHODH's therapeutic relevance in cancer, we have developed novel brequinar-based probes. We disclose a 16-step convergent synthesis of the first brequinar-PROTAC and a four-step approach towards the first mitochondrial-directed brequinar probe. A PROTAC and mitochondria-directed probe of brequinar both possess cytotoxicity that is superior to brequinar in a colony formation assay.