2 research outputs found
Discovery of the Irreversible Covalent FGFR Inhibitor 8‑(3-(4-AcryloylÂpiperazin-1-yl)propyl)-6-(2,6-dichloro-3,5-dimethoxyphenyl)-2-(methylamino)Âpyrido[2,3‑<i>d</i>]Âpyrimidin-7(8<i>H</i>)‑one (PRN1371) for the Treatment of Solid Tumors
Aberrant
signaling of the FGF/FGFR pathway occurs frequently in
cancers and is an oncogenic driver in many solid tumors. Clinical
validation of FGFR as a therapeutic target has been demonstrated in
bladder, liver, lung, breast, and gastric cancers. Our goal was to
develop an irreversible covalent inhibitor of FGFR1–4 for use
in oncology indications. An irreversible covalent binding mechanism
imparts many desirable pharmacological benefits including high potency,
selectivity, and prolonged target inhibition. Herein we report the
structure-based design, medicinal chemistry optimization, and unique
ADME assays of our irreversible covalent drug discovery program which
culminated in the discovery of compound <b>34</b> (PRN1371),
a highly selective and potent FGFR1–4 inhibitor
Discovery of the Irreversible Covalent FGFR Inhibitor 8‑(3-(4-AcryloylÂpiperazin-1-yl)propyl)-6-(2,6-dichloro-3,5-dimethoxyphenyl)-2-(methylamino)Âpyrido[2,3‑<i>d</i>]Âpyrimidin-7(8<i>H</i>)‑one (PRN1371) for the Treatment of Solid Tumors
Aberrant
signaling of the FGF/FGFR pathway occurs frequently in
cancers and is an oncogenic driver in many solid tumors. Clinical
validation of FGFR as a therapeutic target has been demonstrated in
bladder, liver, lung, breast, and gastric cancers. Our goal was to
develop an irreversible covalent inhibitor of FGFR1–4 for use
in oncology indications. An irreversible covalent binding mechanism
imparts many desirable pharmacological benefits including high potency,
selectivity, and prolonged target inhibition. Herein we report the
structure-based design, medicinal chemistry optimization, and unique
ADME assays of our irreversible covalent drug discovery program which
culminated in the discovery of compound <b>34</b> (PRN1371),
a highly selective and potent FGFR1–4 inhibitor