development-68gallium-labeled-d-peptide-pet-tracer-for-imaging

Development of a <sup>68</sup>Gallium-Labeled D-Peptide PET Tracer for Imaging Programmed Death-Ligand 1 Expression

The development of immune checkpoint blockade therapy based on programmed cell death-protein 1 (PD-1)/programmed death-ligand 1 (PD-L1) has revolutionized ...

Chinese Academy of Medical Sciences and Peking Union Medical College

Mutations in RAS/RAF occur in large portion of malignancies and are associated with aggressive clinical behaviors and poor prognosis. Therefore, we developed a novel benzoxazole compound (KZ-001) as a highly potent and selective MEK 1/2 inhibitor. Our efforts were focused on enhancing the activity of the known MEK inhibitor AZD6244 and overcoming the shortcomings existing in current MEK inhibitors. Here we show that compound KZ-001 exhibits approximately 30-fold greater inhibition against BRAF- and KRAS-mutant tumor cells than that of AZD6244. These results were also demonstrated using in vivo xenograft models. Furthermore, pharmacokinetics (PK) analysis was performed for KZ-001, and this compound showed good orally bioavailability (28%) and exposure (AUC = 337 ± 169 ng h/mL). To determine its potential clinical application, the synergistic effect of KZ-001 with other agents was investigated both in vitro and in vivo (xenograft models). KZ-001 exhibited synergistic anti-cancer effect in combination with BRAF inhibitor vemurafenib and a microtubule-stabilizing chemotherapeutic agent docetaxel. In addition, KZ-001 inhibited the MAPK pathway like known MEK inhibitors. In summary, KZ-001, a structurally novel benzoxazole compound, was developed as a MEK inhibitor that has potential for cancer treatment.

Xingkai Wang

State Key Laboratory of Bioactive Substance and Function of Natural Medicines,
Institute of Materia Medica,
State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica

Chinese Academy of Medical Sciences and Peking Union Medical College

Development of a ⁶⁸Gallium-Labeled D-Peptide PET Tracer for Imaging Programmed Death-Ligand 1 Expression

Xingkai Wang

State Key Laboratory of Bioactive Substance and Function of Natural Medicines,Institute of Materia Medica,State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica

Chinese Academy of Medical Sciences and Peking Union Medical College

Development of a 68Gallium-Labeled D-Peptide PET Tracer for Imaging Programmed Death-Ligand 1 Expression

State Key Laboratory of Bioactive Substance and Function of Natural Medicines,
Institute of Materia Medica,
State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica

Development of a ⁶⁸Gallium-Labeled D-Peptide PET Tracer for Imaging Programmed Death-Ligand 1 Expression