4 research outputs found
The Discovery of PLK4 Inhibitors: (<i>E</i>)‑3-((1<i>H</i>‑Indazol-6-yl)methylene)indolin-2-ones as Novel Antiproliferative Agents
The
family of Polo-like kinases is important in the regulation
of mitotic progression; this work keys on one member, namely Polo-like
kinase 4 (PLK4). PLK4 has been identified as a candidate anticancer
target which prompted a search for potent and selective inhibitors
of PLK4. The body of the paper describes lead generation and optimization
work which yielded nanomolar PLK4 inhibitors. Lead generation began
with directed virtual screening, using a ligand-based focused library
and a PLK4 homology model. Validated hits were used as starting points
for the design and discovery of PLK4 inhibitors of novel structure,
namely (<i>E</i>)-3-((1<i>H</i>-indazol-6-yl)Âmethylene)Âindolin-2-ones.
Computational models, based on a published X-ray structure (PLK4 kinase
domain), were used to understand and optimize the in vitro activity
of the series; potent antiproliferative activity was obtained. The
kinase selectivity profile and cell cycle analysis of selected inhibitors
are described. The results of a xenograft study with an optimized
compound <b>50</b> (designated CFI-400437) support the potential
of these novel PLK4 inhibitors for cancer therapy
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which were superseded by the bioisosteric 2-(1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
Discovery of Pyrazolo[1,5‑<i>a</i>]pyrimidine TTK Inhibitors: CFI-402257 is a Potent, Selective, Bioavailable Anticancer Agent
This work describes a scaffold hopping
exercise that begins with
known imidazoÂ[1,2-<i>a</i>]Âpyrazines, briefly explores pyrazoloÂ[1,5-<i>a</i>]Â[1,3,5]Âtriazines, and ultimately yields pyrazoloÂ[1,5-<i>a</i>]Âpyrimidines 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
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