Synthesis and Biological Investigation of (+)-JD1, an Organometallic BET Bromodomain Inhibitor
Hassell-Hart S., Runcie A., Krojer T., Doyle J., Lineham E., Ocasio CA., Neto BAD., Fedorov O., Marsh G., Maple H., Felix R., Banks R., Ciulli A., Picaud S., Filippakopoulos P., Von Delft F., Brennan P., Stewart HJS., Chevassut TJ., Walker M., Austin C., Morley S., Spencer J.
© 2019 American Chemical Society. (+)-JD1, a rationally designed ferrocene analogue of the BET bromodomain (BRD) probe molecule (+)-JQ1, has been synthesized and evaluated in biophysical, cell-based assays as well as in pharmacokinetic studies. It displays nanomolar activity against BRD isoforms, and its cocrystal structure was determined in complex with the first bromodomain of BRD4 and compared with that of (+)-JQ1, a known BRD4 small-molecule probe. At 1 μM concentration, (+)-JD1 was able to inhibit c-Myc, a key driver in cancer and an indirect target of BRD4.