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    Human cathepsin B (CatB) is an important biological target in cancer therapy. In this work, we performed a knowledge-based design approach and the synthesis of a new set of 19 peptide-like nitrile-based cathepsin inhibitors. Reported compounds were assayed against a panel of human cysteine proteases: CatB, CatL, CatK, and CatS. Three compounds (7h, 7i, and 7j) displayed nanomolar inhibition of CatB and selectivity over CatK and CatL. The selectivity was achieved by using the combination of a para biphenyl ring at P3, halogenated phenylalanine in P2 and Thr-O-Bz group at P1. Likewise, compounds 7i and 7j showed selective CatB inhibition among the panel of enzymes studied. We have also described a successful example of bioisosteric replacement of the amide bond for a sulfonamide one [7e → 6b], where we observed an increase in affinity and selectivity for CatB while lowering the compound lipophilicity (ilogP). Our knowledge-based design approach and the respective structure-activity relationships provide insights into the specific ligand-target interactions for therapeutically relevant cathepsins. Copyright © 2020 Elsevier Ltd. All rights reserved.


    Lorenzo Cianni, Fernanda Dos Reis Rocho, Vinícius Bonatto, Felipe Cardoso Prado Martins, Jerônimo Lameira, Andrei Leitão, Carlos A Montanari, Anwar Shamim. Design, synthesis and stepwise optimization of nitrile-based inhibitors of cathepsins B and L. Bioorganic & medicinal chemistry. 2021 Jan 01;29:115827

    PMID: 33254069

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