Anti-tumor Activity of Novel Compounds Targeting BCR-ABL, c-SRC and BCR-ABLT315I in Chronic Myelogenous Leukemia

Chronic myelogenous leukemia (CML) is a hematological stem-cell disorder characterized by the expression of the BCR-ABL fusion protein, a constitutively active tyrosine kinase that causes pathogenesis. The development of tyrosine kinase inhibitors (TKIs) targeting the BCR-ABL oncogene has proven an effective approach to treat CML, but a non-negligible proportion of patients develop a resistance to this class of drugs. Of note, the T315I mutant of BCR-ABL is resistant to all known TKIs, with the noticeable exception of ponatinib. To address this unmet medical need, a new series of compounds was designed and tested for anti-tumor effects against BCR-ABLT315I CML. The effects of three OriBase Pharma compounds (OR1001, OR1002 and OR1003) on the kinase activity of wild-type and mutant BCR-ABL proteins, on cell proliferation and on the growth of subcutaneous xenografts of CML cells in athymic mice were investigated. In vitro, the three compounds were potent inhibitors of both ABL and c-SRC kinases and of the main mutants of ABL, including T315I. The three compounds inhibited the proliferation of cell lines expressing the wild-type and several mutated forms of BCR-ABL, including T315I. Finally, in a mouse xenograft model, OR1001, was found to significantly reduce tumor growth. These data support the potential of OR1001 as an effective therapy for the treatment of de novo and TKI-resistant patients

In Search of Small Molecule Inhibitors Targeting the Flexible CK2 Subunit Interface

Protein kinase CK2 is a tetrameric holoenzyme composed of two catalytic (α and/or α’) subunits and two regulatory (β) subunits. Crystallographic data paired with fluorescence imaging techniques have suggested that the formation of the CK2 holoenzyme complex within cells is a dynamic process. Although the monomeric CK2α subunit is endowed with a constitutive catalytic activity, many of the plethora of CK2 substrates are exclusively phosphorylated by the CK2 holoenzyme. This means that the spatial and high affinity interaction between CK2α and CK2β subunits is critically important and that its disruption may provide a powerful and selective way to block the phosphorylation of substrates requiring the presence of CK2β. In search of compounds inhibiting this critical protein–protein interaction, we previously designed an active cyclic peptide (Pc) derived from the CK2β carboxy-terminal domain that can efficiently antagonize the CK2 subunit interaction. To understand the functional significance of this interaction, we generated cell-permeable versions of Pc, exploring its molecular mechanisms of action and the perturbations of the signaling pathways that it induces in intact cells. The identification of small molecules inhibitors of this critical interaction may represent the first-choice approach to manipulate CK2 in an unconventional way

2-Aminothiazole derivatives as selective allosteric modulators of the protein kinase CK2. Part 2: Structure–based optimization and investigation of effects specific to the allosteric mode of action

International audienc

2-Aminothiazole derivatives as selective allosteric modulators of the protein kinase CK2. Part 1: Identification of an allosteric binding site

International audienc