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-indazol-6-yl)­methylene)­indolin-2-ones, which were superseded by the bioisosteric 2-(1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