LAUSR

Based on a known selective Mcl‐1 inhibitor, 6‐chloro‐3‐(3‐(4‐chloro‐3,5‐dimethylphenoxy)propyl)‐1H‐indole‐2‐carboxylic acid, we applied a fragment‐based approach to obtain new molecules that extended into the p1 pocket of the BH3 groove and then exhibited binding selectivity for the Mcl‐1 over the Bcl‐2 protein. After we deconstructed the 1H‐indole‐2‐carboxylic acid from the parental molecule, a benzenesulfonyl was substituted at the 1‐position to adopt a geometry preferred for accessing the p1 pocket according to the binding mode of the parental molecule identified by X‐ray crystallography. A linear relationship between the free energy of ligand binding (ΔG) and the count of non‐hydrogen heavy atoms (HAC) was maintained during the molecular growing to occupy the p1 pocket. Finally, we not only obtained compound 12 with a 7.5‐fold selectivity to Mcl‐1 (Ki = 0.48 µM by fluorescence polarization) over Bcl‐2 (Ki = 3.6 µM), but also provided evidence that additional occupation of the p1 pocket is more favorable for Mcl‐1 than for Bcl‐2 binding, and contributes more to Mcl‐1 inhibition than occupation of the p2 pocket. Compound 12 exhibited a selective killing ability on Mcl‐1‐dependent cancer cells.