2 research outputs found

    Discovery of Pyrazolo[1,5‑<i>a</i>]pyrimidine TTK Inhibitors: CFI-402257 is a Potent, Selective, Bioavailable Anticancer Agent

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    This work describes a scaffold hopping exercise that begins with known imidazo­[1,2-<i>a</i>]­pyrazines, briefly explores pyrazolo­[1,5-<i>a</i>]­[1,3,5]­triazines, and ultimately yields pyrazolo­[1,5-<i>a</i>]­pyrimidines as a novel class of potent TTK inhibitors. An X-ray structure of a representative compound is consistent with 1<sup>1</sup>/<sub>2</sub> type inhibition and provides structural insight to aid subsequent optimization of in vitro activity and physicochemical and pharmacokinetic properties. Incorporation of polar moieties in the hydrophobic and solvent accessible regions modulates physicochemical properties while maintaining potency. Compounds with enhanced oral exposure were identified for xenograft studies. The work culminates in the identification of a potent (TTK <i>K</i><sub>i</sub> = 0.1 nM), highly selective, orally bioavailable anticancer agent (CFI-402257) for IND enabling studies

    The Discovery of Orally Bioavailable Tyrosine Threonine Kinase (TTK) Inhibitors: 3‑(4-(heterocyclyl)phenyl)‑1<i>H</i>‑indazole-5-carboxamides as Anticancer Agents

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    The acetamido and carboxamido substituted 3-(1<i>H</i>-indazol-3-yl)­benzenesulfonamides are potent TTK inhibitors. However, they display modest ability to attenuate cancer cell growth; their physicochemical properties, and attendant pharmacokinetic parameters, are not drug-like. By eliminating the polar 3-sulfonamide group and grafting a heterocycle at the 4 position of the phenyl ring, potent inhibitors with oral exposure were obtained. An X-ray cocrystal structure and a refined binding model allowed for a structure guided approach. Systematic optimization resulted in novel TTK inhibitors, namely 3-(4-(heterocyclyl)­phenyl)-1<i>H</i>-indazole-5-carboxamides. Compounds incorporating the 3-hydroxy-8-azabicyclo[3.2.1]­octan-8-yl bicyclic system were potent (TTK IC<sub>50</sub> < 10 nM, HCT116 GI<sub>50</sub> < 0.1 μM), displayed low off-target activity (>500×), and microsomal stability (<i>T</i><sub>1/2</sub> > 30 min). A subset was tested in rodent PK and mouse xenograft models of human cancer. Compound <b>75</b> (CFI-401870) recapitulated the phenotype of TTK RNAi, demonstrated in vivo tumor growth inhibition upon oral dosing, and was selected for preclinical evaluation
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