2. Academic Validation
  3. Evaluation of novel pyrazol-4-yl pyridine derivatives possessing arylsulfonamide tethers as c-Jun N-terminal kinase (JNK) inhibitors in leukemia cells

Evaluation of novel pyrazol-4-yl pyridine derivatives possessing arylsulfonamide tethers as c-Jun N-terminal kinase (JNK) inhibitors in leukemia cells

  • Eur J Med Chem. 2023 Sep 15:261:115779. doi: 10.1016/j.ejmech.2023.115779.
Karim I Mersal 1,  Mohammed S Abdel-Maksoud 2,  Eslam M H Ali 3,  Usama M Ammar 4,  Seyed-Omar Zaraei 5,  Md Mamunul Haque 6,  Tanuza Das 7,  Noha F Hassan 8,  Eunice EunKyeong Kim 9,  Jun-Seok Lee 10,  HaJeung Park 11,  Kwan Hyi Lee 12,  Mohammed I El-Gamal 13,  Hee-Kwon Kim 14,  Tamer M Ibrahim 15,  Chang-Hyun Oh 16
Affiliations

Affiliations

  • 1 Pharmaceutical Chemistry Department, Faculty of Pharmacy, Modern University for Technology and Information (MTI), Cairo, 12055, Egypt; University of Science & Technology (UST), Daejeon, Yuseong-gu, 34113, Republic of Korea; Center of Biomaterials, Korea Institute of Science & Technology (KIST School), Seoul, Seongbuk-gu, 02792, Republic of Korea.
  • 2 Medicinal & Pharmaceutical Chemistry Department, Pharmaceutical and Drug Industries Research Institute, National Research Centre NRC (ID: 60014618), Dokki, Giza, 12622, Egypt.
  • 3 Pharmaceutical Chemistry Department, Faculty of Pharmacy, Modern University for Technology and Information (MTI), Cairo, 12055, Egypt; Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, 575 West Stadium Avenue, West Lafayette, IN, 47907, USA.
  • 4 School of Applied Sciences, Edinburgh Napier University, Sighthill Campus, 9 Sighthill Court, Edinburgh, EH11 4BN, United Kingdom.
  • 5 Research Institute for Medical and Health Sciences, University of Sharjah, Sharjah, 27272, United Arab Emirates.
  • 6 Department of Neural and Pain Sciences, School of Dentistry, University of Maryland, Baltimore, MD, 21201, USA.
  • 7 Department of Neurology, School of Medicine, Johns Hopkins University, Baltimore, MD, 21205, USA.
  • 8 Department of Pharmacology and Toxicology, Faculty of Pharmacy, Modern University for Technology and Information (MTI), Cairo, 12055, Egypt.
  • 9 Biomedical Research Institute, Korea Institute of Science and Technology, Seoul, 02792, South Korea.
  • 10 Department of Pharmacology, College of Medicine, Korea University, Seoul, 02841, South Korea.
  • 11 The Herbert Wertheim UF Scripps Institute for Biomedical Innovation & Technology, USA.
  • 12 Center for Advanced Biomolecular Recognition, Korea Institute of Science & Technology (KIST School), Seoul, Seongbuk-gu, 02792, Republic of Korea; KU-KIST Graduate School of Converging Science and Technology, Korea University, Seoul, 02841, Republic of Korea.
  • 13 Research Institute for Medical and Health Sciences, University of Sharjah, Sharjah, 27272, United Arab Emirates; Department of Medicinal Chemistry, College of Pharmacy, University of Sharjah, Sharjah, 27272, United Arab Emirates; Department of Medicinal Chemistry, Faculty of Pharmacy, Mansoura University, Mansoura, 35516, Egypt.
  • 14 Department of Nuclear Medicine, Molecular Imaging & Therapeutic Medicine Research Center, Jeonbuk National University Medical School and Hospital, 20 Geonji-ro, Deokjin-gu, Jeonju, 54907, Republic of Korea; Research Institute of Clinical Medicine of Jeonbuk National University-Biomedical Research Institute of Jeonbuk National University Hospital, 20 Geonji-ro, Deokjin-gu, Jeonju, 54907, Republic of Korea. Electronic address: [email protected].
  • 15 Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Kafrelsheikh University, Kafrelsheikh, P.O. Box 33516, Egypt.
  • 16 University of Science & Technology (UST), Daejeon, Yuseong-gu, 34113, Republic of Korea; Center of Biomaterials, Korea Institute of Science & Technology (KIST School), Seoul, Seongbuk-gu, 02792, Republic of Korea. Electronic address: [email protected].
PMID: 37776574 DOI: 10.1016/j.ejmech.2023.115779
Abstract

A series of 36 pyrazol-4-yl pyridine derivatives (8a-i, 9a-i, 10a-i, and 11a-i) was designed, synthesized, and evaluated for its antiproliferative activity over NCI-60 Cancer cell line panel and inhibitory effect against JNK isoforms (JNK1, JNK2, and JNK3). All the synthesized compounds were tested against the NCI-60 Cancer cell line panel. Compounds 11b, 11c, 11g, and 11i were selected to determine their GI50s and exerted a superior potency over the reference standard SP600125 against the tested cell lines. 11c showed a GI50 of 1.28 μM against K562 leukemic cells. Vero cells were used to assess 11c cytotoxicity compared to the tested Cancer cells. The target compounds were tested against hJNK isoforms in which compound 11e exhibited the highest potency against JNK isoforms with IC50 values of 1.81, 12.7, and 10.5 nM against JNK1, JNK2, and JNK3, respectively. Kinase profiling of 11e showed higher JNK selectivity in 50 kinase panels. Compounds 11c and 11e showed cell population arrest at the G2/M phase, induced early Apoptosis, and slightly inhibited beclin-1 production at higher concentrations in K562 leukemia cells relative to SP600125. NanoBRET assay of 11e showed intracellular JNK1 inhibition with an IC50 of 2.81 μM. Also, it inhibited CYP2D6 and 3A4 with different extent and its hERG activity showed little cardiac toxicity with an IC50 of 4.82 μM. hJNK3 was used as a template to generate the hJNK1 crystal structure to explore the binding mode of 11e (PDB ID: 8ENJ) with a resolution of 2.8 °A and showed a typical type I kinase inhibition against hJNK1. Binding energy scores showed that selectivity of 11e towards JNK1 could be attributed to additional hydrophobic interactions relative to JNK3.

Keywords

Arylsulfonamide; Cancer; JNK; Leukemia; Pyrazole.

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