2 research outputs found
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)Âmethylene)Âindolin-2-ones,
which were superseded by the bioisosteric 2-(1<i>H</i>-indazol-6-yl)ÂspiroÂ[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<sub>N</sub>2 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)Âbenzenesulfonamides
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)Âphenyl)-1<i>H</i>-indazole-5-carboxamides. Compounds incorporating the 3-hydroxy-8-azabicyclo[3.2.1]Âoctan-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