The Discovery of Polo-Like Kinase 4 Inhibitors: Identification of (1<i>R</i>,2<i>S</i>)‑2-(3-((<i>E</i>)‑4-(((<i>cis</i>)‑2,6-Dimethylmorpholino)methyl)styryl)‑1<i>H</i>‑indazol-6-yl)-5′-methoxyspiro[cyclopropane-1,3′-indolin]-2′-one (CFI-400945) as a Potent, Orally Active Antitumor Agent

Previous publications from our laboratory have introduced novel inhibitors of Polo-like kinase 4 (PLK4), a mitotic kinase identified as a potential target for cancer therapy. The search for potent and selective PLK4 inhibitors yielded (<i>E</i>)-3-((1<i>H</i>-indazol-6-yl)­methylene)­indolin-2-ones, which were superseded by the bioisosteric 2-(1<i>H</i>-indazol-6-yl)­spiro­[cyclopropane-1,3′-indolin]-2′-ones, e.g., <b>3</b>. The later scaffold confers improved drug-like properties and incorporates two stereogenic centers. This work reports the discovery of a novel one-pot double S_N2 displacement reaction for the stereoselective installation of the desired asymmetric centers and confirms the stereochemistry of the most potent stereoisomer, e.g., <b>44</b>. Subsequent work keys on the optimization of the oral exposure of nanomolar PLK4 inhibitors with potent cancer cell growth inhibitory activity. A short list of compounds with superior potency and pharmacokinetic properties in rodents and dogs was studied in mouse models of tumor growth. We conclude with the identification of compound <b>48</b> (designated CFI-400945) as a novel clinical candidate for cancer therapy

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

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 IC₅₀ < 10 nM, HCT116 GI₅₀ < 0.1 μM), displayed low off-target activity (>500×), and microsomal stability (<i>T</i>_1/2 > 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