2. Academic Validation
  3. Identification of a novel GSK3β inhibitor involved in abrogating KRas dependent pancreatic tumors in Wnt/beta-catenin and NF-kB dependent manner

Identification of a novel GSK3β inhibitor involved in abrogating KRas dependent pancreatic tumors in Wnt/beta-catenin and NF-kB dependent manner

  • Life Sci. 2024 Aug 15:351:122840. doi: 10.1016/j.lfs.2024.122840.
Mir Owais Ayaz 1,  Aadil Qadir Bhat 1,  Zaheen Akhter 2,  Neetu Badsera 1,  Md Mehedi Hossain 1,  Farheen Showket 1,  Sabra Parveen 1,  Mohmmad Saleem Dar 1,  Harshita Tiwari 2,  Nedhi Kumari 3,  Mahir Bhardwaj 3,  Razak Hussain 4,  Ashutosh Sharma 5,  Mukesh Kumar 6,  Umed Singh 7,  Amit Nargorta 2,  Aravind Singh Kshatri 5,  Utpal Nandi 8,  Satdarshan Pal Monga 9,  P Ramajayan 3,  Parvinder Pal Singh 10,  Mohd Jamal Dar 11
Affiliations

Affiliations

  • 1 Laboratory of Cell and Molecular Biology, Department of Pharmacology, CSIR-Indian Institute of Integrative Medicine, Jammu, India; Academy of Scientific & Innovative Research, Ghaziabad, Uttar Pradesh 201002, India.
  • 2 Academy of Scientific & Innovative Research, Ghaziabad, Uttar Pradesh 201002, India; Natural Products and Medicinal Chemistry Division, CSIR-Indian Institute of Integrative Medicine, Jammu, Jammu and Kashmir, India.
  • 3 Academy of Scientific & Innovative Research, Ghaziabad, Uttar Pradesh 201002, India; Department of Pharmacology, CSIR-Indian Institute of Integrative Medicine, Jammu 180001, India.
  • 4 Department of Entomology, University of Illinois Urbana-Champaign, Urbana, IL 61801, USA.
  • 5 Division of Neuroscience and Aging Biology, CSIR-Central Drug Research Institute CDRI, Lucknow 226031, India.
  • 6 Natural Products and Medicinal Chemistry Division, CSIR-Indian Institute of Integrative Medicine, Jammu, Jammu and Kashmir, India; Medicinal Product Chemistry, Sussex Drug Discovery Centre, School of Life Sciences, University of Sussex, Falmer, Brighton BN1 9QG, United Kingdom of Great Britain and Northern Ireland.
  • 7 Natural Products and Medicinal Chemistry Division, CSIR-Indian Institute of Integrative Medicine, Jammu, Jammu and Kashmir, India; Department f Chemistry, E331 Chemistry Building, The University of Iowa, Iowa City, IA 52242-1294, USA.
  • 8 Academy of Scientific & Innovative Research, Ghaziabad, Uttar Pradesh 201002, India; Department of Pharmacology, CSIR-Indian Institute of Integrative Medicine, Jammu 180001, India; Bose Institute, Unified Academic Campus, Kolkata 700032, India.
  • 9 Pittsburgh Liver Research Center, School of Medicine, University of Pittsburgh, Pittsburgh, USA.
  • 10 Academy of Scientific & Innovative Research, Ghaziabad, Uttar Pradesh 201002, India; Natural Products and Medicinal Chemistry Division, CSIR-Indian Institute of Integrative Medicine, Jammu, Jammu and Kashmir, India. Electronic address: ppsingh@iiim.res.in.
  • 11 Laboratory of Cell and Molecular Biology, Department of Pharmacology, CSIR-Indian Institute of Integrative Medicine, Jammu, India; Academy of Scientific & Innovative Research, Ghaziabad, Uttar Pradesh 201002, India. Electronic address: jamal@iiim.res.in.
PMID: 38876185 DOI: 10.1016/j.lfs.2024.122840
Abstract

Pancreatic Cancer is an aggressive malignancy with a poor survival rate because it is difficult to diagnose the disease during its early stages. The currently available treatments, which include surgery, chemotherapy and radiation therapy, offer only limited survival benefit. Pharmacological interventions to inhibit Glycogen Synthase Kinase-3beta (GSK3β) activity is an important therapeutic strategy for the treatment of pancreatic Cancer because GSK3β is one of the key factors involved in the onset, progression as well as in the acquisition of chemoresistance in pancreatic Cancer. Here, we report the identification of MJ34 as a potent GSK3β inhibitor that significantly reduced growth and survival of human mutant KRas dependent pancreatic tumors. MJ34 mediated GSK3β inhibition was seen to induce Apoptosis in a β-catenin dependent manner and downregulate NF-kB activity in MiaPaCa-2 cells thereby impeding cell survival and anti-apoptotic processes in these cells as well as in the xenograft model of pancreatic Cancer. In vivo acute toxicity and in vitro cardiotoxicity studies indicate that MJ34 is well tolerated without any adverse effects. Taken together, we report the discovery of MJ34 as a potential drug candidate for the therapeutic treatment of mutant KRas-dependent human cancers through pharmacological inhibition of GSK3β.

Keywords

GSK3β; KRas; NF-kB signaling; Pancreatic cancer; Wnt/beta-catenin signaling.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-161751
    GSK-3β/α Inhibitor