Han, Youngsun Sengupta, Sandip Lee, Byung Joo Cho, Hanna Kim, Jiknyeo Choi, Hwan Geun Dash, Uttam Kim, Jin Hyoung Kim, Nam Doo Kim, Jeong Hun Sim, Taebo 2024-01-19T19:01:54Z 2024-01-19T19:01:54Z 2022-01-10 2019-10-24 0022-2623 https://pubs.kist.re.kr/handle/201004/119429 We synthesized 11 novel L-783277 derivatives, in which a structure rigidifying phenyl ring is incorporated into the 14-membered chiral resorcylic acid lactone system. The SAR study with these substances demonstrated that 17 possesses excellent kinase selectivity against a panel of 335 kinases in contrast to L-783277 and inhibits VEGFR3, VEGFR2, and FLT3 with single-digit nanomolar IC50 values. Also, we found that 21, a stereoisomer of 17, has excellent potency (IC50 = 9 nM) against VEGFR3 and selectivity over VEGFR2 and FLT3. 17, a potent dual VEGFR3 and VEGFR2 inhibitor, effectively suppresses both lymphangiogenesis and angiogenesis in a 3D-microfluidic tumor lymphangiogenesis assay and in vivo corneal assay while SAR131675 blocks only lymphangiogenesis. In addition, 17 blocks the endothelial tube formation and suppresses proliferation of PHE tumor vascular model. 17 will be a valuable templatefor developing therapeutically active and selective substances that target both lymphangiogenesis and angiogenesis. English AMER CHEMICAL SOC STEREOSELECTIVE-SYNTHESIS INHIBITOR POTENT FLT3 BEVACIZUMAB ANTITUMOR EFFICACY RECEPTOR ESTERS MOUSE Identification of a Unique Resorcylic Acid Lactone Derivative That Targets Both Lymphangiogenesis and Angiogenesis Article 10.1021/acs.jmedchem.9b01025 1 JOURNAL OF MEDICINAL CHEMISTRY, v.62, no.20, pp.9141 - 9160 JOURNAL OF MEDICINAL CHEMISTRY 62 20 9141 9160 scie scopus 000492801800015 2-s2.0-85073194155 Chemistry, Medicinal Pharmacology & Pharmacy Article STEREOSELECTIVE-SYNTHESIS INHIBITOR POTENT FLT3 BEVACIZUMAB ANTITUMOR EFFICACY RECEPTOR ESTERS MOUSE