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 (AUC0–∞ = 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.
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Key words: benzoxazole compound, MEK inhibitor, RAF/RAS mutant cancer, synergism, high potency Additional Supporting Information may be found in the online version of this article. Disclosure of Potential Conflicts of Interest: No conflicts of interest were disclosed by the authors. Grant sponsor: CAMS Innovation Fund for Medical Science from the Chinese Academy of Medical Sciences & Peking Union Medical College; Grant number: CIFMS, 2017-I2M-3-019; Grant sponsor: Fundamental Research Fund for CAMS & PUMC; Grant number: 2016ZX310199; Grant sponsor: Innovation Team Funding from the Institute of Radiation Medicine, Chinese Academy of Medical Sciences & Peking Union Medical College; Grant number: 1649 DOI: 10.1002/ijc.32119 History: Received 18 Sep 2018; Accepted 20 Dec 2018; Online 10 Jan 2019 Correspondence to: Hongqi Tian, Tianjin Key Laboratory of Radiation Medicine and Molecular Nuclear Medicine, Institute of Radiation Medicine, Chinese Academy of Medical Sciences and Peking Union Medical College, No. 238 Baidi Road, Nankai District, Tianjin 300192, China, Tel.: +86-22-65378920, Fax: 022-65378920, E-mail: firstname.lastname@example.org
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- benzoxazole compound
- high potency
- MEK inhibitor
- RAF/RAS mutant cancer