Design, synthesis, and biological evaluation of novel aminopyrimidinylisoindolines as AXL kinase inhibitors

• Published in: Bioorganic & medicinal chemistry letters Vol. 28; no. 23-24; pp. 3761 - 3765
• Main Authors: Choi, Min Jung, Roh, Eun Joo, Hur, Wooyoung, Lee, So Ha, Sim, Taebo, Oh, Chang-Hyun, Lee, Sun-Hwa, Kim, Jong Seung, Yoo, Kyung Ho
• Format: Journal Article
• Language: English
• Published: OXFORD Elsevier Ltd 15.12.2018; Elsevier
• Subjects: Amination; Aminopyrimidinylisoindolines; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Antiproliferative activity; AXL kinase; Axl Receptor Tyrosine Kinase; Cell Line, Tumor; Cell Proliferation - drug effects; Chemistry; Chemistry, Medicinal; Chemistry, Organic; Drug Design; Drug Screening Assays, Antitumor; Enzyme inhibitory activity; HeLa Cells; Humans; Inhibitors; Isoindoles - chemical synthesis; Isoindoles - chemistry; Isoindoles - pharmacology; Life Sciences & Biomedicine; Neoplasms - drug therapy; Neoplasms - metabolism; Pharmacology & Pharmacy; Physical Sciences; Protein Kinase Inhibitors - chemical synthesis; Protein Kinase Inhibitors - chemistry; Protein Kinase Inhibitors - pharmacology; Proto-Oncogene Proteins - antagonists & inhibitors; Proto-Oncogene Proteins - metabolism; Pyrimidines - chemical synthesis; Pyrimidines - chemistry; Pyrimidines - pharmacology; Receptor Protein-Tyrosine Kinases - antagonists & inhibitors; Receptor Protein-Tyrosine Kinases - metabolism; Science & Technology; TAM family; AXL kinase; Inhibitors; Enzyme inhibitory activity; Antiproliferative activity; Aminopyrimidinylisoindolines; TAM family; CELLS; RECEPTOR TYROSINE KINASES; TARGETS; CANCER
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2018.10.013

[Display omitted] •Six compounds showed potent inhibitory activities against AXL kinase.•Most compounds showed good antiproliferative activities against HeLa cell line.•1u exhibited extremely excellent efficacy (IC50 = <0.00050 μM) against AXL kinase.•1u showed the best combination of enzyme inhibitory and antiproliferative activities. A novel series of aminopyrimidinylisoindoline derivatives 1a-w having an aminopyrimidine scaffold as a hinge region binding motif were designed and synthesized. Among them, six compounds showed potent inhibitory activities against AXL kinase with IC50 values of submicromolar range. Especially, compound 1u possessing (4-acetylpiperazin-1-yl)phenyl moiety exhibited extremely excellent efficacy (IC50 = <0.00050 μM). Their in vitro antiproliferative activities were tested over five cancer cell lines. Most compounds showed good antiproliferative activities against HeLa cell line. The kinase panel profiling of 50 different kinases and the selected inhibitory activities for the representative compound 1u were carried out. The compound 1u exhibited excellent inhibitory activities (IC50 = <0.00050, 0.025, and 0.050 μM for AXL, MER, and TYRO3, respectively) against TAM family, together with potent antiproliferative activity against MV4-11 cell line (GI50 = 0.10 μM) related to acute myeloid leukemia (AML).