1802220-02-5

Product Details:

CasNo： 1802220-02-5

Molecular Formula： C18H18FN5O2

Purity： 99%

Synonyms: TPX-0005; TPX 0005; TPX0005; CS-2479; Repotrectinib(TPX-005); Repotrectinib; Repotrectinib,TPX-0005; TPX-0005; 1,15-Etheno-1H-pyrazolo[4,3-f][1,4,8,10]benzoxatriazacyclotridecin-4(5H)-one,11-fluoro-6,7,13,14-tetrahydro-7,13-dimethyl-,(7S,13R)-
Density: 1.46±0.1 g/cm3
Solubility: DMSO:35.0(Max Conc. mg/mL);98.5(Max Conc. mM)
                 Ethanol:10.0(Max Conc. mg/mL);28.1(Max Conc. mM)
Color: White to off-white
Form: A crystalline solid
Pka: 10.79±0.60
Storage temp.: Store at -20°C

Binding Mode：
The cocrystal structures of repotrectinib with TRK proteins are yet to be reported. However, a docking model with TRKA suggests that the pyrazole nitrogen forms hydrogen bonds with Met592 in the hinge area. The fluorophenyl group, positioned in a hydrophobic pocket, aligns perpendicularly to the macrocycle, and the lactam oxygen atom engages in a water-mediated hydrogen bond with Met592 in the hinge region.
          

Description:
Ropotrectinib is a nextgeneration ROS1 inhibitor, a novel three-dimensional macrocyle with a much smaller size (MW <370) than current ROS1 inhibitors. It was specifically designed to overcome resistance mutations. Preclinical studies have shown activity against gatekeeper and solvent mutations, including G2032R, D2033N, L2026M, S1986F/Y, L1951R, and kinases involved in bypass signaling such as focal adhesion kinase, SRC proto-oncogene, and non-receptor tyrosine kinase [102, 103].
 

Biological Activity:
Ropotrectinib is a potent inhibitor targeting solvent-front mutations (SFMs) of ROS1, pan-TRK, and ALK. It effectively inhibits the kinase activity of wild-type ROS1, TRKA-C, and ALK, along with their SFMs, with IC50 values ranging from 0.071 to 4.46 nM. The compound shows high potency against ROS1 and TRKA-C, with approximately 15-fold selectivity over ALK.