4 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
Structure-Based Drug Design of RN486, a Potent and Selective Bruton’s Tyrosine Kinase (BTK) Inhibitor, for the Treatment of Rheumatoid Arthritis
Structure-based
drug design was used to guide the optimization
of a series of selective BTK inhibitors as potential treatments for
Rheumatoid arthritis. Highlights include the introduction of a benzyl
alcohol group and a fluorine substitution, each of which resulted
in over 10-fold increase in activity. Concurrent optimization of drug-like
properties led to compound <b>1</b> (RN486) (J. Pharmacol. Exp. Ther. 2012, 341, 90),
which was selected for advanced preclinical characterization based
on its favorable properties
Pyrrolopyrazines as Selective Spleen Tyrosine Kinase Inhibitors
We describe the discovery of several pyrrolopyrazines
as potent and selective Syk inhibitors and the efforts that eventually
led to the desired improvements in physicochemical properties and
human whole blood potencies. Ultimately, our mouse model revealed
unexpected toxicity that precluded us from further advancing this
series