122nd General Meeting of the KCS

Type Poster Presentation
Area Medicinal Chemistry
Room No. Grand Ballroom
Time 10월 18일 (목요일) 11:00~12:30
Code MEDI.P-278
Subject Synthesis of Novel Aminoquinazolinylisoindolines and Their Enzyme Inhibitory and Anticancer Activities
Authors Juseung Kim, Juri Suh, Sunwoo Lim, Jongseung Kim1, Kyung Ho Yoo2,*
Chemical Kinomics Research Center, Korea Institute of Science and Technology / Department of Chemistry, Korea University, Korea
1Department of Chemistry, Korea University, Korea
2Chemical Kinomics Research Center, Korea Institute of Science and Technology, Korea
Abstract In recent years, AXL kinase has emerged as a key facilitator of immune escape and drug-resistance by eliminating intercellular antibodies, regulating the release and secretion of cytokines. AXL has been implicated as a cancer driver and correlated with poor survival in numerous aggressive tumors including TNBC, AML, NSCLC, pancreatic cancer, and ovarian cancer. The ACK1 tyrosine kinase is aberrantly activated, amplified, or mutated in many types of human cancers, including prostate, breast, pancreatic, ovarian, and lung cancers. Therefore, AXL and ACK1 have been proposed as the attractive targets for cancer therapeutics and a number of small molecule inhibitors have been developed. The purpose of this study is to develop the potent compounds as dual kinase inhibitors against AXL and ACK1. Based on the structural features of TP-0903 and TAE-684 as AXL and ACK1 inhibitors, a novel series of aminoquinazolinylisoindoline derivatives were designed and synthesized. Their in vitro enzyme inhibitory and antiproliferative activities were tested. Among them, several compounds showed good inhibitory activities against AXL and ACK1. Many compounds showed potent antiproliferative activities against MV4-11 and A549 cell lines with GI50 values of sub-micromolar range. In our series, compound 1m possessing 4-methylpiperazinylphenylamino moiety exhibited good inhibitory activities (IC50 = 0.887 and 6.16μM, respectively) against AXL and ACK1, together with potent antiproliferative activities (GI50 = 0.0237, 0.762, and 0.752μM for MV4-11, A549, and HeLa, respectively).
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