1-Methyl-3-((4-(quinolin-4-yloxy)phenyl)amino)-1H-pyrazole-4-carboxamide derivatives as new rearranged during Transfection (RET) kinase inhibitors capable of suppressing resistant mutants in solvent-front regions

Unraveling the Promise of RET Inhibitors in Precision Cancer Therapy by Targeting RET Mutations

“…If other hydrophilic groups such as morpholinyl were installed at the 7-position, the obtained compounds showed a significant 6-to-24-fold decrease in the inhibitory ability against G810 C/R. 159 This marked reduction in inhibitory ability was attributed to the installation of a elongated side chain, possibly inducing steric effects and diminishing its impact on resistant mutants. Compound 37 exhibited a dosedependent suppression of RET activation and downstream signaling in Ba/F3-CCDC6−RET G810C/R cells.…”

“…In a xenograft model of CCDC6−RET G810C cells, compound 37 displayed notable antitumor efficacy, achieving a tumor growth inhibition value of 66.9% at a daily dose of 30 mg/kg via intraperitoneal administration. 159 However, it showed relatively poor pharmacokinetic parameters, requiring further optimization. Overall, compound 37 provides a novel quinoline scaffold to address resistance mediated by solvent-front mutations against current RET inhibitors.…”

“…SAR studies revealed crucial insights into structural modifications affecting the inhibitory potency. Reduction in the size of hydrophobic substituents at the adamantyl position led to a loss of potency . The installation of a 2′-fluoro group on the middle phenyl ring emerged as a superior choice, exhibiting enhanced activity in comparison to alternative substituents such as chloro, cyano, or methoxy groups at the same position.…”

“…Reduction in the size of hydrophobic substituents at the adamantyl position led to a loss of potency. 159 The installation of a 2′-fluoro group on the middle phenyl ring emerged as a superior choice, exhibiting enhanced activity in comparison to alternative substituents such as chloro, cyano, or methoxy groups at the same position. If other hydrophilic groups such as morpholinyl were installed at the 7-position, the obtained compounds showed a significant 6-to-24-fold decrease in the inhibitory ability against G810 C/R.…”

“…Compound 37 demonstrated potent suppression of WT RET, boasting an IC 50 value of 13.7 nM (Figure A) . It also exhibited strong inhibition of proliferation in BaF3 cells expressing various oncogenic fusions of RET kinase with solvent-front mutations, including CCDC6–RET-G810C, CCDC6–RET-G810R, KIF5B–RET-G810C, and KIF5B–RET-G810R, with IC 50 values of 15.4, 53.2, 54.2, and 120.0 nM, respectively.…”