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

Ahmed Elkamhawy; Sora Paik; Eslam M H Ali; Ahmed H E Hassan; So Jin Kang; Kyeong Lee; Eun Joo Roh

doi:10.3390/ph15091050

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

Pharmaceuticals (Basel). 2022 Aug 25;15(9):1050. doi: 10.3390/ph15091050.

Authors

Ahmed Elkamhawy^{1

2}, Sora Paik³, Eslam M H Ali^{4

5}, Ahmed H E Hassan⁶, So Jin Kang⁷, Kyeong Lee¹, Eun Joo Roh^{3

8}

Affiliations

¹ BK21 FOUR Team and Integrated Research Institute for Drug Development, College of Pharmacy, Dongguk University-Seoul, Goyang 10326, Korea.
² Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt.
³ Chemical and Biological Integrative Research Center, Korea Institute of Science and Technology (KIST), Seoul 02792, Korea.
⁴ Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, 575 West Stadium Avenue, West Lafayette, IN 47907, USA.
⁵ Pharmaceutical Chemistry Department, Faculty of Pharmacy, Modern University for Technology and Information (MTI), Cairo 12055, Egypt.
⁶ Department of Medicinal Chemistry, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt.
⁷ Department of Biotechnology, Graduate School Korea University, Seoul 02841, Korea.
⁸ Division of Bio-Medical Science & Technology, University of Science and Technology, Daejeon 34113, Korea.

Abstract

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 µM 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 µM. 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 ~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.

Keywords: DAPK1 inhibitors; anti-proliferative activity; aryl carboxamides; death-associated protein kinase 1 (DAPK1); kinase inhibitors.

Grants and funding

Grant No. 2E 31624/Korea Institute of Science and Technology