Journal
BIOORGANIC & MEDICINAL CHEMISTRY
Volume 28, Issue 12, Pages -Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmc.2020.115555
Keywords
c-Met kinase inhibitor; 1,6-Naphthyridone; VEGFR-2 selectivity; Antitumor efficacy
Funding
- National Natural Science Foundation of China [21272086]
- Science and Technology Program of Wuhan, China [2019020701011460]
- Fundamental Research Funds for the Central Universities [CCNU19QN073, CCNU18TS009]
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New N-substituted-3-phenyl-1,6-naphthyridinone derivatives are designed and synthesized, based on structural modification of our previously reported compound 3. Extensive enzyme-based SAR studies and PK evaluation led to the discovery of compound 4r, with comparable c-Met potency to that of Cabozantinib and high VEGFR-2 selectivity, while Cabozantinib displayed no VEGFR-2 selectivity. More importantly, at oral doses of 45 mg/kg (Q.D.), compound 4r exhibits significant tumor growth inhibition (93%) in a U-87MG human gliobastoma xenograft model. The promising selectivity against VEGFR-2 and excellent tumor growth inhibition of compound 4r suggest that it could be used as a new lead molecule for further discovery of selective type II c-Met inhibitors.
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