Elkamhawy, Ahmed Paik, Sora Ali, Eslam M. H. Hassan, Ahmed H. E. Kang, So Jin Lee, Kyeong Roh, Eun Joo 2024-01-19T11:03:56Z 2024-01-19T11:03:56Z 2022-10-11 2022-09 1424-8247 https://pubs.kist.re.kr/handle/201004/114580 Death-associated protein kinase 1 (DAPK1) is a serine/threonine protein kinase involved in diverse fundamental cellular processes such as apoptosis and autophagy. DAPK1 isoform plays an essential role as a tumor suppressor and inhibitor of metastasis. Consequently, DAPK1 became a promising target protein for developing new anti-cancer agents. In this work, we present the rational design and complete synthetic routes of a novel series of eighteen aryl carboxamide derivatives as potential DAPK1 inhibitors. Using a custom panel of forty-five kinases, a single dose of 10 mu M of the picolinamide derivative 4a was able to selectively inhibit DAPK1 kinase by 44.19%. Further investigations revealed the isonicotinamide derivative 4q as a promising DAPK1 inhibitory lead compound with an IC50 value of 1.09 mu M. In an in vitro anticancer activity assay using a library of 60 cancer cell lines including blood, lung, colon, CNS, skin, ovary, renal, prostate, and breast cancers, four compounds (4d, 4e, 4o, and 4p) demonstrated high anti-proliferative activity with mean % GI similar to 70%. Furthermore, the most potent DAPK1 inhibitor (4q) exhibited remarkable activity against leukemia (K-562) and breast cancer (MDA-MB-468) with % GI of 72% and 75%, respectively. English Multidisciplinary Digital Publishing Institute (MDPI) Identification of Novel Aryl Carboxamide Derivatives as Death-Associated Protein Kinase 1 (DAPK1) Inhibitors with Anti-Proliferative Activities: Design, Synthesis, In Vitro, and In Silico Biological Studies Article 10.3390/ph15091050 1 Pharmaceuticals, v.15, no.9 Pharmaceuticals 15 9 Y scie scopus 000857067600001 Chemistry, Medicinal Pharmacology & Pharmacy Pharmacology & Pharmacy Article ALZHEIMERS-DISEASE SMALL-MOLECULE ACTIVATION DISCOVERY APOPTOSIS death-associated protein kinase 1 (DAPK1) kinase inhibitors DAPK1 inhibitors anti-proliferative activity aryl carboxamides