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Small molecule activators of HRI kinase: A new class of anti-cancer therapeutics and biomarker for cancer patient selection
Technology:
Small molecule activators of HRI kinase - A new class of anti-cancer therapeutics and method for cancer patient selection
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New class of anti-cancer therapeutics: Recent studies have shown that HRI is expressed in tissues other than hematopoietic cells. For the first time, Harvard researchers have demonstrated that activation of this kinase interferes with proliferation of cancer cells in vitro and tumor growth in vivo. This suggests that this class of compounds might become a starting point for new anti-cancer therapeutics. At the same time, the compounds will be used in research laboratories to better understand the role of translation initiation cellular development, differentiation, and proliferation.
Method for cancer patient selection: HRI can also be used as a biomarker to select cancer patients for treatment with diarylurea and diarylthiourea compounds. The Aktas lab has developed an assay to determine the expression level of HRI in any given cancer cell. Patients with cancer cells that have a higher level of HRI expression will respond more effectively to treatment of cancer with diarylurea and diarylthiourea compounds.
Innovations and Advantages
Background: Translation initiation plays a critical role cellular homeostasis, proliferation and differentiation. A key regulatory step in the translation initiation cascade is the assembly of a ternary complex formed by the eukaryotic translation initiation factor 2 (eIF2), GTP and the initiator methionine tRNA (Met-tRNAi). This molecular machinery is highly conserved and many effectors can modulate translation initiation in a variety of species – from unicellular parasites to higher mammals.
eIF2α and ER Stress: The endoplasmic reticulum is the major signal transducing organelle that sense and responds to changes in homeostasis. Conditions that interfere with ER function, collectively called ER stress, is induced by accumulation of unfolded protein aggregates or increased protein traffic. Accumulation of unfolded protein aggregates triggers eIF2 phosphorylation attenuates general protein synthesis and induces cell death in both a caspase-dependent and a caspase-independent manner. Recent research indicates cytoprotection in cancers through a modulated ER stress pathway. By inducing eIF2α phosphorylation via HRI kinase activation (described further below), anti-proliferative phenotypes in vitro have been shown in cancer cell lines.
Small molecule screen for ternary complex effectors: Researchers in Aktas laboratory have executed a high-throughput screen for small molecule modulators of ternary complex abundance. For this, they took advantage of the paradoxical increase in the translation of the activating transcription factor-4 (ATF-4) upon depletion of the ternary complex. Murine cells were transfected with dual luciferase plasmid coding for ATF-4-reporter or control-reporter. Increase in the ATF-4 reporter to control reporter ratio signified increase in ATF-4 translation and ternary complex depletion. Corresponding compounds were included into the follow-up assays.
A new class ternary complex inhibitors: Analysis of the screening data revealed a high prevalence of a certain class of compounds. Subsequent mechanistic studies indicate the mechanism of action and possible therapeutic use of the compounds:
• The mechanism of action: Researchers have determined that the small molecules in this class activate Heme Regulated Inhibitor (HRI) kinase, since RNAi knock-down of the enzyme interfered with activities of the hits. The kinase is known to phosphorylate eIF2α subunit of the initiation factor, which, in turn, inactivates the whole ternary complex. They also demonstrated direct interaction of compounds with HRI.
• Compounds are low-toxic: Three-week treatment of mice with the compounds did not result in any outward signs of toxicity, or abnormal blood parameters, or histological appearance of any organs.
• N,N'-diarylureas inhibit cancer cell proliferation in vitro growth of mammary tumors in vivo. Researchers determined that hit compounds inhibit proliferation of cancer cells in vitro and that this dependent on HRI-dependent phosphorylation of eIF2a. They further demonstrated that anti-proliferative activity of hit compounds correlates with the expression of HRI. Finally they determined that hit compounds inhibit growth of mammary tumors in mouse model of human breast cancer. Thinhibition of tumor growth was associated with phosphorylation of eIF2a in the tumors.
Additional Information
Intellectual Property Status: Patent(s) pending
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Inventor(s):
Aktas, Huseyin
Chorev, Michael
Halperin, Jose A.
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For further information, please contact:
Michal Preminger, Director of Business Development
(617) 432-0920
Reference Harvard Case #3439