TPX-0005

Details:

CAS number :1802220-02-5

English name :TPX-0005

English alias :Repotrectinib; TPX-005; Ropotrectinib; CS-2479; TPX-0005; Loprotinib; PX0005(Ropotrectinib); TPX0005(Ropotrectinib); Repotrectinib,TPX-0005; TPX-0005,Repotrectinib

CBNumber:CB83312797

Molecular formula :C18H18FN5O2

Molecular weight :355.37

Density :1.46±0.1g/cm3(Predicted)

Storage condition :Storeat-20°C

Solubility :DMSO:35.0(MaxConc.mg/mL); 98.5 (MaxConc. MM) Ethanol: 10.0 Chemicalbook (MaxConc. Mg/mL); 28.1(MaxConc.mM) Form :Acrystallinesolid

Acidity coefficient (pKa):10.79±0.60(Predicted)

Color :Whitetooff-white

Lopritinib (TPX-0005) is a fourth-generation ALK inhibitor developed by TPTherapeutics, a broad-spectrum ALK, ROS1 and TRK inhibitor, which mainly targets a variety of acquired mutations. Including ALKG1202R, ROS1G2032R and TRKAG595R mutations. On June 28, 2017, TPTherapeutics announced that the FDA has granted orphan drug status to its investigational clinical drug compound TPX-0005 for NSCLC patients with ALK, ROS1, or NTRK oncogene rearrangements. TPX-0005 is currently in a Phase 1/2, open-label, multicenter clinical trial evaluating safety, tolerability, pharmacokinetics, and antitumor activity in a population of patients with advanced solid tumors with ALK, ROS1, or NTRK1-3 rearrangement mutations.

Repotrectinib (TPX-0005) is a novel ALK/ROS1/TRK inhibitor with IC50 of 1.01 nM for WT ALK, 1.26 nM for ALK(G1202R) and 1.08 nM for ALK(L1196M), respectively. It is also a potent SRC inhibitor with an IC50 of 5.3 nM.

TPX-0005 has a compact three-dimensional macrocyclic molecular structure with a molecular weight of 355.37, which is smaller than all existing ALK and ROS1 inhibitors. As we all know, there are several mechanisms of ALK inhibitor resistance in general: secondary resistance mutation in ALK kinase domain, copy number amplification of ALK fusion gene, activation of bypass and downstream pathways, epithelial mesenchymal transformation, etc. The compact small molecule structure of TPX-Chemicalbook0005 allows it to bind to the central binding site within ATP and avoid steric hindrance caused by mutations outside the ATP binding site, i.e. avoid interference from clinical resistance mutations. In addition, TPX-0005 has a smaller molecular weight than all existing ALK and ROS1 inhibitors and is likely to have the same powerful blood-brain barrier penetration ability as Lorlatinib.