2. Academic Validation
  3. Targeting N-myristoylation for therapy of B-cell lymphomas

Targeting N-myristoylation for therapy of B-cell lymphomas

  • Nat Commun. 2020 Oct 22;11(1):5348. doi: 10.1038/s41467-020-18998-1.
Erwan Beauchamp 1 2,  Megan C Yap 1 2,  Aishwarya Iyer 1,  Maneka A Perinpanayagam 1 2,  Jay M Gamma 3,  Krista M Vincent 4,  Manikandan Lakshmanan 5,  Anandhkumar Raju 6 7,  Vinay Tergaonkar 6 7,  Soo Yong Tan 6 7,  Soon Thye Lim 8,  Wei-Feng Dong 4,  Lynne M Postovit 4,  Kevin D Read 9,  David W Gray 9,  Paul G Wyatt 9,  John R Mackey 2 4,  Luc G Berthiaume 10 11
Affiliations

Affiliations

  • 1 Department of Cell Biology, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, T6G 2H7, AB, Canada.
  • 2 Pacylex Pharmaceuticals Inc., Edmonton, AB, Canada.
  • 3 Departments of Medicine, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, T6G 2H7, AB, Canada.
  • 4 Departments of Oncology, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, T6G 2H7, AB, Canada.
  • 5 Mouse Models of Human Cancer Unit, Institute of Molecular and Cell Biology, 61 Biopolis Drive, Proteos, 138673, Singapore.
  • 6 Advanced Molecular Pathology Lab, Institute of Molecular and Cell Biology, 61 Biopolis Drive, Proteos, Singapore, 138673.
  • 7 Department of Pathology, National University of Singapore, Singapore, Singapore.
  • 8 Department of Medical Oncology, National Cancer Centre Singapore, 11 Hospital Drive, Outram Road, Singapore, 169610, Singapore.
  • 9 Drug Discovery Unit, School of Life Sciences, University of Dundee, James Black Centre, Dow Street, Dundee, DD1 5EH, UK.
  • 10 Department of Cell Biology, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, T6G 2H7, AB, Canada. [email protected].
  • 11 Pacylex Pharmaceuticals Inc., Edmonton, AB, Canada. [email protected].
PMID: 33093447 DOI: 10.1038/s41467-020-18998-1
Abstract

Myristoylation, the N-terminal modification of proteins with the fatty acid myristate, is critical for membrane targeting and cell signaling. Because Cancer cells often have increased N-myristoyltransferase (NMT) expression, NMTs were proposed as anti-cancer targets. To systematically investigate this, we performed robotic Cancer cell line screens and discovered a marked sensitivity of hematological Cancer cell lines, including B-cell lymphomas, to the potent pan-NMT inhibitor PCLX-001. PCLX-001 treatment impacts the global myristoylation of lymphoma cell proteins and inhibits early B-cell receptor (BCR) signaling events critical for survival. In addition to abrogating myristoylation of Src family kinases, PCLX-001 also promotes their degradation and, unexpectedly, that of numerous non-myristoylated BCR effectors including c-Myc, NFκB and P-ERK, leading to Cancer cell death in vitro and in xenograft models. Because some treated lymphoma patients experience relapse and die, targeting B-cell lymphomas with a NMT inhibitor potentially provides an additional much needed treatment option for lymphoma.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-147308
    99.05%, NMT Inhibitor