(R,S)-SIM1 (3a), which has inverted stereochemistry at one of the two BET ligands making it inactive at binding one of the two BET bromodomains (Fig. ) , and the non-degrading negative control isomer cis-SIM1 (3b) (Fig. and Supplementary Information) . While the synthesis of cis-SIM1 was straightforward as with its trans diastereomer, initial attempts to synthesize (R,S)-SIM1 compound by using half equivalent of BET ligand at the final coupling step failed to produce the desired 1:1 coupling with an acceptable yield. Therefore, we revised the synthetic route to allow subsequent, independent coupling steps with (+)-JQ1 (9) first, followed by (-)-JQ1 (9a) (Supplementary Information). Upon successful synthesis, (R,S)-SIM1 was tested for degradation activity and found to behave similarly to MZ1 and less potently than SIM1 for degradation of all BET family members (Fig. ).