2. Academic Validation
  3. Identification of novel piperazine-tethered phthalazines as selective CDK1 inhibitors endowed with in vitro anticancer activity toward the pancreatic cancer

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.
Laila Akl 1,  Amer Ali Abd El-Hafeez 2,  Tamer M Ibrahim 1,  Rofaida Salem 1,  Hala Mohamed M Marzouk 3,  Ramadan A El-Domany 4,  Pradipta Ghosh 5,  Wagdy M Eldehna 6,  Sahar M Abou-Seri 7
Affiliations

Affiliations

  • 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: aam002@health.ucsd.edu.
  • 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: wagdy2000@gmail.com.
  • 7 Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Cairo University, Kasr El-Aini Street, Cairo, P.O. Box 11562, Egypt. Electronic address: sahar.shaarawy@pharma.cu.edu.eg.
PMID: 36095992 DOI: 10.1016/j.ejmech.2022.114704
Abstract

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.

Keywords

CDK inhibitors; Cell cycle; Dinaciclib; Pancreatic ductal adenocarcinoma; Phthalazines.

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