2 research outputs found
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