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The BMS BET inhibitor, BMS-986158, is in a Ph. I/IIa trial in advanced cancers. During the optimization of the molecule from a carbazole hit, the authors employed a bold scaffold-hopping strategy involving changing the direction of the carbazole core in order to better access a hydrophobic region of the target. The proposed new binding mode was confirmed by X-ray co-crystallography. The molecule’s triazole ring also interestingly binds in a manner in which both unsubstituted N atoms appear to be engaged as hydrogen bond acceptors to different hydrogen bond donors in the protein (Asn140 for one, a water-mediated H-bond to Tyr97 for the other).