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  • Title: Discovery of potent, highly selective covalent irreversible BTK inhibitors from a fragment hit.
    Author: Qiu H, Liu-Bujalski L, Caldwell RD, Follis AV, Gardberg A, Goutopoulos A, Grenningloh R, Head J, Johnson T, Jones R, Mochalkin I, Morandi F, Neagu C, Sherer B.
    Journal: Bioorg Med Chem Lett; 2018 Sep 15; 28(17):2939-2944. PubMed ID: 30122225.
    Abstract:
    Bruton's Tyrosine Kinase (BTK) is a member of the TEC kinase family that is expressed in cells of hematopoietic lineage (e.g., in B cells, macrophages, monocytes, and mast cells). Small molecule covalent irreversible BTK inhibitor targeting Cys481 within the ATP-binding pocket, for example ibrutinib, has been applied in the treatment of B-cell malignancies. Starting from a fragment hit, we discovered a novel series of potent covalent irreversible BTK inhibitors that occupy selectivity pocket of the active site of the BTK kinase domain. Guided by X-ray structures and a fragment-based drug design (FBDD) approach, we generated molecules showing comparable cellular potency to ibrutinib and higher kinome selectivity against undesirable off-targets like EGFR.
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