Deng, Xianming Okram, Barun Ding, Qiang Zhang, Jianming Choi, Yongmun Adrian, Francisco J. Wojciechowski, Amy Zhang, Guobao Che, Jianwei Bursulaya, Badry Cowan-Jacob, Sandra W. Rummel, Gabriele Sim, Taebo Gray, Nathanael S. 2024-01-20T18:31:14Z 2024-01-20T18:31:14Z 2021-09-04 2010-10-14 0022-2623 https://pubs.kist.re.kr/handle/201004/131007 Inhibition of Bcr-Abl kinase activity by imatinib for the treatment of chronic myeloid leukemia (CM I.) currently serves as the paradigm or targeting dominant oncogenes with small molecules. We recently reported the discovery of GNF (1) and GNF (2) as selective non-ATP competitive inhibitors of cellular Bcr-Abl kinase activity that target the myristate binding site. Here, we used cell-based structure-activity relationships to guide the optimization and diversification of ligands that are capable of binding to the myristate binding site and rationalize the findings based upon an Abl-compound 1 cocrystal. We elucidate the structure-activity relationships required to obtain potent antiproliferative activity against Bcr-Abl transformed cells and report the discovery of new compounds (544, 5h, 6a, 14d, and 21j-1) that display improved potency or pharmacological properties. This work demonstrates that a variety of structures can effectively target the myristate binding site and provides new leads for developing drugs that can target this binding site. English AMER CHEMICAL SOC CHRONIC MYELOGENOUS LEUKEMIA BCR-ABL QUANTITATIVE-ANALYSIS KINASE INHIBITOR RESISTANCE IMATINIB PYRIMIDINES MECHANISMS BMS-354825 DISCOVERY Expanding the Diversity of Allosteric Ber-Abl Inhibitors Article 10.1021/jm100555f 1 JOURNAL OF MEDICINAL CHEMISTRY, v.53, no.19, pp.6934 - 6946 JOURNAL OF MEDICINAL CHEMISTRY 53 19 6934 6946 scie scopus 000282544800011 2-s2.0-77957930406 Chemistry, Medicinal Pharmacology & Pharmacy Article CHRONIC MYELOGENOUS LEUKEMIA BCR-ABL QUANTITATIVE-ANALYSIS KINASE INHIBITOR RESISTANCE IMATINIB PYRIMIDINES MECHANISMS BMS-354825 DISCOVERY