Discovery and development of potent and selective dual NUAK/MARK inhibitors as Hippo pathway modulators for the treatment of cancer

  • Eur J Med Chem. 2026 Jul 5:311:118798. doi: 10.1016/j.ejmech.2026.118798.
David Smil  1 ,  Yong Liu  2 ,  Tao Xin  2 ,  Taira Kiyota  2 ,  Ahmed Aman  3 ,  Julie Grouleff  2 ,  Laurent Hoffer  2 ,  Dhananjay C Joshi  2 ,  Mohammad R Inanlou  4 ,  Siyuan Song  4 ,  Daniel Y L Mao  5 ,  Abiodun A Ogunjimi  5 ,  Victor Pau  5 ,  Fiona D Chini  6 ,  Igor Kurinov  7 ,  Ying Zhang  8 ,  Anh Thu Nguyen  5 ,  Jeffrey L Wrana  8 ,  Frank Sicheri  9 ,  Liliana Attisano  10 ,  David Uehling  2 ,  Rima Al-Awar  11 ,  Methvin B Isaac  2
Affiliations
  • 1. Drug Discovery Program, Ontario Institute for Cancer Research, 661 University Avenue, MaRS Centre, West Tower, Toronto, Ontario, M5G 0A3, Canada. Electronic address: [email protected].
  • 2. Drug Discovery Program, Ontario Institute for Cancer Research, 661 University Avenue, MaRS Centre, West Tower, Toronto, Ontario, M5G 0A3, Canada.
  • 3. Drug Discovery Program, Ontario Institute for Cancer Research, 661 University Avenue, MaRS Centre, West Tower, Toronto, Ontario, M5G 0A3, Canada; Leslie Dan Faculty of Pharmacy, University of Toronto, 144 College Street, Toronto, Ontario, M5S 3M2, Canada.
  • 4. Department of Biochemistry, Donnelly Centre, University of Toronto, Toronto, Ontario, M5S 3E1, Canada.
  • 5. Lunenfeld-Tanenbaum Research Institute, Sinai Health System, Toronto, Ontario, M5G 1X5, Canada.
  • 6. Department of Biomedical and Molecular Science, Queen's University, Kingston, Ontario, K7L2V7, Canada.
  • 7. Department of Chemistry and Chemical Biology, Cornell University, NE-CAT, Argonne, IL, USA.
  • 8. Lunenfeld-Tanenbaum Research Institute, Sinai Health System, Toronto, Ontario, M5G 1X5, Canada; Department of Molecular Genetics, University of Toronto, Toronto, Ontario, M5S 1A8, Canada.
  • 9. Lunenfeld-Tanenbaum Research Institute, Sinai Health System, Toronto, Ontario, M5G 1X5, Canada; Department of Molecular Genetics, University of Toronto, Toronto, Ontario, M5S 1A8, Canada; Department of Biochemistry, University of Toronto, Toronto, Ontario, M5S 1A8, Canada.
  • 10. Department of Biochemistry, Donnelly Centre, University of Toronto, Toronto, Ontario, M5S 3E1, Canada. Electronic address: [email protected].
  • 11. Drug Discovery Program, Ontario Institute for Cancer Research, 661 University Avenue, MaRS Centre, West Tower, Toronto, Ontario, M5G 0A3, Canada; Department of Pharmacology and Toxicology, University of Toronto, Medical Sciences Building, 1 King's College Circle, Toronto, Ontario, M5S 1A8, Canada.
PMID: 41936796 DOI: 10.1016/j.ejmech.2026.118798
Abstract

Restoring the tumor suppressive activity of the Hippo signaling pathway lost through dysregulation of the NUAK1/2 and MARK2/3 kinase axis and downstream transcriptional effectors YAP/TAZ has emerged as a new modality for the treatment of several human cancers. Small molecule inhibition of NUAK1/2 and MARK2/3 constitutes a rational approach to block YAP/TAZ nuclear translocation and prevent a pro-oncogenic gene expression program. Modest structural changes to lead compound OICR14489, discovered through computational studies using a NUAK2 homology model, afforded the potent and selective dual NUAK1/2 and MARK2/3 inhibitor OICR16422. Further optimization led to inhibitor OICR19451, which produced an increase in YAP phosphorylation and enhanced cytoplasmic YAP/TAZ localization. In vitro growth inhibition of several Cancer cell lines, coupled with the robust in vivo pharmacokinetic properties of OICR19451 marked it as an advanced tool compound suitable for in vivo evaluation. Accordingly, in an orthotopic model of highly metastatic breast Cancer, MDA-MB-231 tumor-bearing mice treated with OICR19451 showed reduced metastases, tumor encapsulation and an overall increase in survival indicative of favorable Hippo pathway modulation.

Keywords
Bioavailable; Inhibitor; Kinase; MARK; NUAK; Selective; YAP.
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