4 research outputs found
Design, Synthesis, and Biological Evaluation of 2‑Oxo-3,4-dihydropyrimido[4,5‑<i>d</i>]pyrimidinyl Derivatives as New Irreversible Epidermal Growth Factor Receptor Inhibitors with Improved Pharmacokinetic Properties
Structural
optimization of a series of 2-oxo-3,4-dihydropyrimidoÂ[4,5-<i>d</i>]Âpyrimidinyl compounds, potential new irreversible EGFR
inhibitors, was performed to improve pharmacokinetic properties of
the compounds. This led to compound <b>2v</b> with improved
aqueous solubility and good pharmacokinetic properties which at the
nanomolar level potently inhibits gefitinib-resistant EGFR<sup>L858R/T790M</sup> kinase and displays strong antiproliferative activity against H1975
nonsmall cell lung cancer cells. The new inhibitor also shows promising
antitumor efficacy in a murine EGFR<sup>L858R/T790M</sup>-driven H1975
xenograft model without effect on body weight. These studies provide
new lead compounds for further development of drugs for treatment
of gefitinib-resistant nonsmall cell lung cancer patients
Design, Synthesis, and Biological Evaluation of Potent and Selective PROTAC Degraders of Oncogenic KRAS<sup>G12D</sup>
KRASG12D, the most frequent KRAS oncogenic
mutation,
is a promising target for cancer therapy. Herein, we report the design,
synthesis, and biological evaluation of a series of KRASG12D PROTACs by connecting the analogues of MRTX1133 and the VHL ligand.
Structural modifications of the linker moiety and KRAS inhibitor part
suggested a critical role of membrane permeability in the degradation
activity of the KRASG12D PROTACs. Mechanism studies with
the representative compound 8o demonstrated that the
potent, rapid, and selective degradation of KRASG12D induced
by 8o was via a VHL- and proteasome-dependent manner.
This compound selectively and potently suppressed the growth of multiple
KRASG12D mutant cancer cells, displayed favorable pharmacokinetic
and pharmacodynamic properties in mice, and showed significant antitumor
efficacy in the AsPC-1 xenograft mouse model. Further optimization
of 8o appears to be promising for the development of
a new chemotherapy for KRASG12D-driven cancers as the complementary
therapeutic strategy to KRAS inhibition
Design, Synthesis, and Biological Evaluation of Potent and Selective PROTAC Degraders of Oncogenic KRAS<sup>G12D</sup>
KRASG12D, the most frequent KRAS oncogenic
mutation,
is a promising target for cancer therapy. Herein, we report the design,
synthesis, and biological evaluation of a series of KRASG12D PROTACs by connecting the analogues of MRTX1133 and the VHL ligand.
Structural modifications of the linker moiety and KRAS inhibitor part
suggested a critical role of membrane permeability in the degradation
activity of the KRASG12D PROTACs. Mechanism studies with
the representative compound 8o demonstrated that the
potent, rapid, and selective degradation of KRASG12D induced
by 8o was via a VHL- and proteasome-dependent manner.
This compound selectively and potently suppressed the growth of multiple
KRASG12D mutant cancer cells, displayed favorable pharmacokinetic
and pharmacodynamic properties in mice, and showed significant antitumor
efficacy in the AsPC-1 xenograft mouse model. Further optimization
of 8o appears to be promising for the development of
a new chemotherapy for KRASG12D-driven cancers as the complementary
therapeutic strategy to KRAS inhibition
Design, Synthesis, and Biological Evaluation of Potent and Selective PROTAC Degraders of Oncogenic KRAS<sup>G12D</sup>
KRASG12D, the most frequent KRAS oncogenic
mutation,
is a promising target for cancer therapy. Herein, we report the design,
synthesis, and biological evaluation of a series of KRASG12D PROTACs by connecting the analogues of MRTX1133 and the VHL ligand.
Structural modifications of the linker moiety and KRAS inhibitor part
suggested a critical role of membrane permeability in the degradation
activity of the KRASG12D PROTACs. Mechanism studies with
the representative compound 8o demonstrated that the
potent, rapid, and selective degradation of KRASG12D induced
by 8o was via a VHL- and proteasome-dependent manner.
This compound selectively and potently suppressed the growth of multiple
KRASG12D mutant cancer cells, displayed favorable pharmacokinetic
and pharmacodynamic properties in mice, and showed significant antitumor
efficacy in the AsPC-1 xenograft mouse model. Further optimization
of 8o appears to be promising for the development of
a new chemotherapy for KRASG12D-driven cancers as the complementary
therapeutic strategy to KRAS inhibition