12 research outputs found
Multielectron photoexcitations in x-ray-absorption spectra of elements
By removing the structural x-ray-absorption fine-structure signal from K-edge absorption spectra of 4pelements from Ga to Br in chalcogenide glasses and other samples, the pure atomic absorption is recovered. Its main components are shake-up and shake-off channels of the [1s3p] and [1s3d] group. The [1s3p]4p shake-up channel is observed to close off along the series as the 4p shell is progressively filled
JDQ443, a Structurally Novel, Pyrazole-Based, Covalent Inhibitor of KRAS<sup>G12C</sup> for the Treatment of Solid Tumors
Rapid emergence of tumor resistance via RAS pathway reactivation
has been reported from clinical studies of covalent KRASG12C inhibitors. Thus, inhibitors with broad potential for combination
treatment and distinct binding modes to overcome resistance mutations
may prove beneficial. JDQ443 is an investigational covalent KRASG12C inhibitor derived from structure-based drug design followed
by extensive optimization of two dissimilar prototypes. JDQ443 is
a stable atropisomer containing a unique 5-methylpyrazole core and
a spiro-azetidine linker designed to position the electrophilic acrylamide
for optimal engagement with KRASG12C C12. A substituted
indazole at pyrazole position 3 results in novel interactions with
the binding pocket that do not involve residue H95. JDQ443 showed
PK/PD activity in vivo and dose-dependent antitumor activity in mouse
xenograft models. JDQ443 is now in clinical development, with encouraging
early phase data reported from an ongoing Phase Ib/II clinical trial
(NCT04699188)
JDQ443, a Structurally Novel, Pyrazole-Based, Covalent Inhibitor of KRAS<sup>G12C</sup> for the Treatment of Solid Tumors
Rapid emergence of tumor resistance via RAS pathway reactivation
has been reported from clinical studies of covalent KRASG12C inhibitors. Thus, inhibitors with broad potential for combination
treatment and distinct binding modes to overcome resistance mutations
may prove beneficial. JDQ443 is an investigational covalent KRASG12C inhibitor derived from structure-based drug design followed
by extensive optimization of two dissimilar prototypes. JDQ443 is
a stable atropisomer containing a unique 5-methylpyrazole core and
a spiro-azetidine linker designed to position the electrophilic acrylamide
for optimal engagement with KRASG12C C12. A substituted
indazole at pyrazole position 3 results in novel interactions with
the binding pocket that do not involve residue H95. JDQ443 showed
PK/PD activity in vivo and dose-dependent antitumor activity in mouse
xenograft models. JDQ443 is now in clinical development, with encouraging
early phase data reported from an ongoing Phase Ib/II clinical trial
(NCT04699188)