Pyrroformyl-containing 2,4-diaminopyrimidine derivatives as a new optimization strategy of ALK inhibitors combating mutations |
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| Institution: | 1. Department of Neurochemistry, Cuban Center for Neurosciences, Street. 190 e/ 25 and 27, Cubanacan, Playa, Havana, CP 11600, Cuba;2. Institute of Neurobiology (INB), Developmental Neurobiology and Neurophysiology, UNAM Juriquilla Querétaro, Mexico;3. Biomedical and Pharmaceutical Chemistry, Uruguayan Centre of Molecular Imaging (CUDIM), Montevideo, Uruguay;4. Center of Genetic Engineering and Biotechnology (CIGB), Ave 31 e/ 158 and 190, Havana, CP10600, Cuba;1. Department of Medicinal Chemistry, School of Pharmacy, Xi′an Jiaotong University, Xi′an, Shaanxi, 710061, PR China;2. Department of Pharmacology, School of Basic Medical Science, Xi′an Jiaotong University, Xi′an, Shaanxi, 710061, PR China;1. Department of Biological Chemistry, Korea University of Science and Technology, 113 Gwahangno, Yuseong-gu, Daejeon 305-333, Republic of Korea;2. Chemical Kinomics Research Center, Korea Institute of Science and Technology, Seoul 130-650, Republic of Korea;3. Specific Organ Branch, National Cancer Center, 323 Ilsan-ro, Ilsandong-gu, Goyang-si, Gyeonggi-do 410-769, Republic of Korea;1. Key Laboratory of Structure-Based Drug Design and Discovery, Ministry of Education, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenhe District, Shenyang, 110016, China;2. Department of Pharmacology, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenhe District, Shenyang, 110016, China;3. Syngenta, Jealott''s Hill International Research Centre, Bracknell, Berkshire RG42 6EY, UK;1. Key Laboratory of Structure-Based Drug Design and Discovery, Ministry of Education, Shenyang Pharmaceutical University, Shenyang, 110016, China;2. Department of Pharmacology, Shenyang Pharmaceutical University, Shenyang, 110016, China |
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| Abstract: | Aiming to identify new optimization strategy effective for ALK-mutations, two series of pyrroformyl-containing 2,4-diaminopyrimidine compounds (11a-o, 12a-o) were designed, synthesized and evaluated for their anti-proliferative activities against three cancer cell lines in vitro by MTT assay. The biological evaluations on cellular assay resulted in discovery of compound 11k, which performed considerable activity with IC50 value of 0.034 μM against H2228 cell. Meanwhile, 11k exhibited outstanding enzymatic inhibitory potency with IC50 values of 1.9 nM and 3.1 nM against ALKWT and ALKL1196M, respectively, surpassing the reference ceritinib (IC50 = 2.4 nM and 7.6 nM). Ultimately, the binding mode of 11k with ALK was established to explore the SARs. Overall, 11k was considered as a promising ALK inhibitor for mutation treatment. |
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| Keywords: | ALK inhibitor 2 4-Diaminopyrimidine Pyrroformyl L1196M mutation Synthesis Biological evaluations |
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