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Cell Chem Biol. 2019 Mar 21;26(3):331-339.e3. doi: 10.1016/j.chembiol.2018.11.011. Epub 2019 Jan 10.

HTiP: High-Throughput Immunomodulator Phenotypic Screening Platform to Reveal IAP Antagonists as Anti-cancer Immune Enhancers.

Author information

1
Department of Pharmacology and Emory Chemical Biology Discovery Center, Emory University School of Medicine, Atlanta, GA 30322, USA.
2
Department of Pharmacology and Emory Chemical Biology Discovery Center, Emory University School of Medicine, Atlanta, GA 30322, USA; Department of Urology, The First Affiliated Hospital, Medical School of Xi'an Jiaotong University, Xi'an, Shannxi 710061, People's Republic of China.
3
Department of Pharmacology and Emory Chemical Biology Discovery Center, Emory University School of Medicine, Atlanta, GA 30322, USA; Department of Hematology and Medical Oncology and Winship Cancer Institute, Emory University, Atlanta, GA 30322, USA. Electronic address: hfu@emory.edu.

Abstract

Protein- and cell-based immunotherapeutic agents have revolutionized cancer treatment. However, small-molecule immunomodulators with favorable pharmacological properties for reaching intracellular targets remain to be developed. To explore the vast chemical space, a robust method that recapitulates the complex cancer-immune microenvironment in a high-throughput format is essential. To address this critical gap, we developed a high-throughput immunomodulator phenotypic screening platform, HTiP, which integrates the immune and cancer cell co-culture system with imaging- and biochemical-based multiplexed readouts. Using the HTiP platform, we have demonstrated its capability in modeling an oncogenic KRAS mutation-driven immunosuppressive phenotype. From a bioactive chemical library, multiple structurally distinct compounds were identified, all of which target the same class of proteins, inhibitor of apoptosis protein (IAP). IAP has demonstrated roles in cancer immunity. Identification of IAP antagonists as potent anti-tumor immune enhancers provides strong validating evidence for the use of the HTiP platform to discover small-molecule immunomodulators.

KEYWORDS:

IAP; IAP antagonist; KRAS mutation; inhibitor of apoptosis protein; small-molecule immunomodulator; tumor and immune cell co-culture

PMID:
30639259
PMCID:
PMC6501824
[Available on 2020-03-21]
DOI:
10.1016/j.chembiol.2018.11.011

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