2. Academic Validation
  3. Dimers of isatin derived α-methylene-γ-butyrolactone as potent anti-cancer agents

Dimers of isatin derived α-methylene-γ-butyrolactone as potent anti-cancer agents

  • Bioorg Med Chem Lett. 2022 Jun 1:65:128713. doi: 10.1016/j.bmcl.2022.128713.
Sandeep Rana 1,  Smit Kour 2,  Smitha Kizhake 2,  Hannah M King 2,  Jayapal Reddy Mallareddy 2,  Adam J Case 3,  Tom Huxford 4,  Amarnath Natarajan 5
Affiliations

Affiliations

  • 1 Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE 68198, United States. Electronic address: sandeep.rana@nih.gov.
  • 2 Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE 68198, United States.
  • 3 Departments of Cellular & Integrative Physiology, University of Nebraska Medical Center, Omaha, NE 68198, United States.
  • 4 Structural Biochemistry Laboratory, Department of Chemistry & Biochemistry, San Diego State University, San Diego, CA 92182, United States.
  • 5 Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE 68198, United States; Departments of Pharmaceutical Sciences, University of Nebraska Medical Center, Omaha, NE 68198, United States; Departments of Genetics Cell Biology and Anatomy, University of Nebraska Medical Center, Omaha, NE 68198, United States; Departments of Fred and Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE 68198, United States. Electronic address: anatarajan@unmc.edu.
PMID: 35367592 DOI: 10.1016/j.bmcl.2022.128713
Abstract

The IKK-NFκB complex is a key signaling node that facilitates activation of gene expression in response to extracellular signals. The kinase IKKβ and the transcription factor RELA have been targeted by covalent modifiers that bind to surface exposed cysteine residues. A common feature in well characterized covalent modifiers of RELA and IKKβ is the Michael acceptor containing α-methylene-γ-butyrolactone functionality. Through synthesis and evaluation of a focused set of α-methylene-γ-butyrolactone containing spirocyclic dimers (SpiDs) we identified SpiD3 as an Anticancer agent with low nanomolar potency. Using cell-free and cell-based studies we show that SpiD3 is a covalent modifier that generates stable RELA containing high molecular weight complexes. SpiD3 inhibits TNFα-induced IκBα phosphorylation resulting in the blockade of RELA nuclear translocation. SpiD3 induces Apoptosis, inhibits colony formation and migration of Cancer cells. The NCI-60 cell line screen revealed that SpiD3 potently inhibits growth of leukemia cell lines, making it a suitable pre-therapeutic lead for hematological malignancies.

Keywords

Cancer; Irreversible inhibitor; NFκB pathway; RELA inhibitor; Spirocyclic compounds; α-methylene-γ-butyrolactone.

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