2. Academic Validation
  3. Dissecting Polypharmacology in Phenotypic Screening to Resolve Ferroptotic and Necrotic Cell-Death Mechanisms

Dissecting Polypharmacology in Phenotypic Screening to Resolve Ferroptotic and Necrotic Cell-Death Mechanisms

  • ACS Med Chem Lett. 2026 Mar 24;17(4):876-883. doi: 10.1021/acsmedchemlett.6c00020.
Kenichi Shimada 1 2,  Elisabet Gregori-Puigjane 3 4,  Michael E Stokes 1,  Rachid Skouta 5,  Brent R Stockwell 1 6
Affiliations

Affiliations

  • 1 Department of Biological Sciences, Columbia University, New York, New York 10027, United States.
  • 2 Currently: Laboratory of Systems Pharmacology, Harvard Medical School, Boston, Massachusetts 02115, United States.
  • 3 Department of Pharmaceutical Chemistry, University of California, San Francisco, California 94158, United States.
  • 4 Currently: Chemotargets SL, C. Baldiri Reixac 4-8, 08028 Barcelona, Spain.
  • 5 Departments of Biology and Chemistry, University of Massachusetts, Amherst, Massachusetts 01003, United States.
  • 6 Department of Chemistry, Department of Pathology and Cell Biology, Herbert Irving Comprehensive Cancer Center, Digestive and Liver Disease Research Center, Irving Institute for Cancer Dynamic, Columbia University, New York, New York 10027, United States.
PMID: 41982731 DOI: 10.1021/acsmedchemlett.6c00020
Abstract

Small molecules frequently induce heterogeneous cell-death programs, complicating the mechanistic interpretation and optimization. Here, we investigate the ferroptotic and necrotic activities of the lethal small molecule CIL56 and related analogs. Although structurally similar, these compounds induce chemically separable death phenotypes. A phenotypic suppressor screen further identified distinct sets of small molecules that selectively attenuate ferroptotic or necrotic death. Classification of suppressor compounds based on shared ligand-based target predictions suggested nonoverlapping groups of candidate protein targets linked to each death modality. Together, these results show that integrating phenotypic screening with suppressor classification and target prediction can improve the interpretability of small-molecule phenotypic screens by prioritizing candidate proteins and pathways underlying the observed biological response.

Keywords

chemical annotation; ferroptosis; nonapoptotic cell death; phenotypic cell-based screening; polypharmacology; similarity ensemble approach.

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