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

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