Scale-up and optimization of the synthesis of dual CBP/BRD4 inhibitor ISOX-DUAL

ISOX-DUAL is a dual inhibitor of CBP/p300 (IC 50 = 0.65 μM) and BRD4 (IC 50 = 1.5 μM) bromodomains, and a useful chemical probe for epigenetic research. Aspects of the published synthetic route to this compound and its analogues are small-scale, poor-yielding or simply unamenable to scale-up without optimization. Herein we describe the development of a refined synthesis that circumvents the challenges of the original report, with notable improvements to several of the key synthetic transformations. Moreover, a general Suzuki Miyaura protocol for the late stage installation of alternative dimethyl-isoxazole acetyl-lysine (KAc) binding motifs is presented. A much improved synthesis, in significantly higher overall yield, for this important chemical probe is reported. Problematic steps have been revisited, closely examined and rectified.