121st General Meeting of the KCS

Type Poster Presentation
Area Medicinal Chemistry
Room No. Event Hall
Time 4월 19일 (목요일) 11:00~12:30
Code MEDI.P-630
Subject Novel 3,6-disubstituted indazole derivatives, multi-targeted kinase inhibitors to overcome anaplastic thyroid cancer
Authors Seunghye Choi, Injae Shin, Taebo Sim1,*
Korea University, Korea
1Chemical Kinomics Research Center, Korea Institute of Science and Technology, Korea
Abstract Anaplastic thyroid cancer (ATC) in thyroid cancer is rare, lethal malignancy solid tumor with median survival of 3 to 6 months. It carries a poor prognosis without any effective treatment for therapy been established. It is true that BRAF V600E mutation is the importance in oncogenesis of thyroid cancer but inhibition of only the BRAF V600E is not enough for proliferation arrest against BRAF V600E mutated papillary (PTC) and undifferentiated thyroid cancer such as ATC and Poor differentiated thyroid cancer (PDTC). Sorafenib, a multitargeted kinase inhibitor, inhibits the angiogenesis and growth of orthotopic anaplastic thyroid carcinoma xenografts in nude mice. These reports is to prove that a multi-target kinase inhibitor is need to overcome ATC. In this respect, we approached designing BRAF V600E inhibitors starting from molecular modeling to identify synthesized 3,6-disubstituted indazole scaffold as a novel therapeutic agent that targets dysregulated signal pathways in ATC. Most of the compounds showed potent anti-proliferative activity against 8505C (BRAF V600E), SW1736 (BRAF V600E) and HTH-7 (wtBRAF) cell lines, the most promising compound. Compound 7g was inhibit to BRAF, BRAF V600E, CRAF, RET, YES/YES1, PDGFRa, c-Src, FMS with an IC50 value of 13.6 nM, 1.97 nM, 2 nM, <0.5 nM, 5.02 nM, 4 nM, 28 nM, and 20.8 nM as multi-targeted kinase inhibitor. As expected, PLX4032 had low effect on ATC cell lines such as 8505C, SW1736 and HTH-7, but 7g showed remarkable anti-proliferative activities. On the basis of its superior in vitro and in vivo profile more than PLX4032. To that end, we analyzed the effects of 7g on human thyroid cancer cell lines to determine whether this compound is useful in the treatment of ATC.
E-mail seunghye80@kist.re.kr