cfi-400945 and Neoplasms

The identification of novel anticancer agents with high efficacy and low toxicity has always been an intriguing topic in medicinal chemistry. The unique structural features of spirooxindoles together with diverse biological activities have made them promising structures in new drug discovery. “Among spirooxindoles, CFI-400945, recently discovered by Sampson et al., is a potent PLK4 inhibitor, which has entered phase I clinical trials for the treatment of solid tumors. However, questions remain as to whether PLK4 is the only relevant therapeutic target for CFI-400945. To highlight this significant progress of CFI-400945 in last two years, this review centers on the identification from a focused kinase library, structural optimizations and strategies involved, structure-activity relationships, modes of action, target validation, chemical synthesis and, more importantly, the kinase selectivity between PLK4 and other targets [corrected].

Topics: Administration, Oral; Animals; Antineoplastic Agents; Drug Discovery; Humans; Indazoles; Indoles; Neoplasms; Protein Serine-Threonine Kinases; Structure-Activity Relationship

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The search for potent and selective PLK4 inhibitors yielded (E)-3-((1Hindazol-6-yl)methylene)indolin-2-ones, which were superseded by the bioisosteric 2-(1H-indazol-6-yl)spiro[cyclopropane-1,3'-indolin]-2'-ones, e.g., 3. The later scaffold confers improved drug-like properties and incorporates two stereogenic centers. This work reports the discovery of a novel one-pot double SN2 displacement reaction for the stereoselective installation of the desired asymmetric centers and confirms the stereochemistry of the most potent stereoisomer, e.g., 44. 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 48 (designated CFI-400945) as a novel clinical candidate for cancer therapy.

Topics: Administration, Oral; Animals; Antineoplastic Agents; Biological Availability; Cell Line, Tumor; Cell Survival; Dogs; Dose-Response Relationship, Drug; Drug Discovery; Female; HCT116 Cells; Humans; Indazoles; Indoles; Male; MCF-7 Cells; Mice, Nude; Mice, SCID; Models, Chemical; Molecular Structure; Neoplasms; Protein Kinase Inhibitors; Protein Serine-Threonine Kinases; Rats; Structure-Activity Relationship; Xenograft Model Antitumor Assays