Identification of novel piperazine-tethered phthalazines as selective CDK1 inhibitors endowed with in vitro anticancer activity toward the pancreatic cancer
- Eur J Med Chem. 2022 Aug 31;243:114704. doi: 10.1016/j.ejmech.2022.114704.
- 1. Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Kafrelsheikh University, Kafrelsheikh, P.O. Box 33516, Egypt.
- 2. Department of Cellular and Molecular Medicine, University of California San Diego, La Jolla, CA, USA; Pharmacology and Experimental Oncology Unit, Cancer Biology Department, National Cancer Institute, Cairo University, Cairo, Egypt. Electronic address: [email protected].
- 3. Department of Cellular and Molecular Medicine, University of California San Diego, La Jolla, CA, USA; Department of Biochemistry, Faculty of Medicine, Minia University, El-Minia, 61519, Egypt.
- 4. Department of Microbiology and Immunology, Faculty of Pharmacy, Kafrelsheikh University, Kafrelsheikh, P.O. Box 33516, Egypt.
- 5. Department of Cellular and Molecular Medicine, University of California San Diego, La Jolla, CA, USA; Department of Medicine, University of California San Diego, La Jolla, CA, 92093, USA; Moores Comprehensive Cancer Center, University of California San Diego, La Jolla, CA, 92093, USA.
- 6. Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Kafrelsheikh University, Kafrelsheikh, P.O. Box 33516, Egypt. Electronic address: [email protected].
- 7. Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Cairo University, Kasr El-Aini Street, Cairo, P.O. Box 11562, Egypt. Electronic address: [email protected].
Pharmacologic inhibition of the oncogenic protein kinases using small molecules is a promising strategy to combat several human malignancies. CDK1 is an example of such a valuable target for the management of pancreatic ductal adenocarcinomas (PDAC); its overexpression in PDAC positively correlates with the size, histological grade and tumor aggressiveness. Here we report the identification of novel series of 1-piperazinyl-4-benzylphthalazine derivatives (8a-g, 10a-i and 12a-d) as promising Anticancer agents with CDK1 inhibitory activity. The anti-proliferative activity of these agents was first screened on a panel of 11 cell lines representing 5 cancers (pancreas, melanoma, leukemia, colon and breast), and then confirmed on two CDK1-overexpressing PDAC cell lines (MDA-PATC53 and PL45 cells). Phthalazines 8g, 10d and 10h displayed potent activity against MDA-PATC53 (IC50 = 0.51, 0.88 and 0.73 μM, respectively) and PL45 (IC50 = 0.74, 1.14 and 1.00 μM, respectively) cell lines. Furthermore, compounds 8g, 10d and 10h exhibited potent and selective inhibitory activity toward CDK1 with IC50 spanning in the range 36.80-44.52 nM, whereas they exerted weak inhibitory effect on CDK2, CDK5, Axl, PTK2B, FGFR, JAK1, IGF1R and BRAF kinases. Western blotting of CDK1 in MDA-PATC53 cells confirmed the ability of target phthalazines to diminish the CDK1 levels, and cell cycle analyses revealed their ability to arrest the cell cycle at G2/M phase. In conclusion, a panel of potent and selective CDK1 inhibitors were identified which can serve as lead compounds for designing further CDK1 inhibitors.