Glioma, especially the most aggressive type glioblastoma multiforme, is a malignant cancer of the central nervous system with a poor prognosis. Traditional treatments are mainly surgery combined with radiotherapy and chemotherapy, which is still far from satisfactory. Therefore, it is of great clinical significance to find new therapeutic agents. Serving as an inhibitor of differentiation, protein ID2 (inhibitor of DNA binding 2) plays an important role in neurogenesis, neovascularization and malignant development of gliomas. It has been shown that ID2 affects the malignant progression of gliomas through different mechanisms. In this study, a pharmacophore-based virtual screening was carried out and 16 hit compounds were purchased for pharmacological evaluations on their ID2 inhibitory activities. Based on the cytotoxicity of these small-molecule compounds, two compounds were shown to effectively inhibit the viability of glioma cells in the micromolar range. Among them, AK-778-XXMU was chosen for further study due to its better solubility in water. A SPR (Surface Plasma Resonance) assay proved the high affinity between AK-778-XXMU and ID2 protein with the K_D value as 129 nM. The plausible binding mode of ID2 was studied by molecular docking and it was found to match AGX51 very well in the same binding site. Subsequently, the cancer-suppressing potency of the compound was characterized both in vitro and in vivo. The data demonstrated that compound AK-778-XXMU is a potent ID2 antagonist which has the potential to be developed as a therapeutic agent against glioma.

01 Oct 2019·Cell ReportsQ1 · BIOLOGY

A Small-Molecule Pan-Id Antagonist Inhibits Pathologic Ocular Neovascularization

Q1 · BIOLOGY

ArticleOA

Author: Arakawa, Tsutomu ; Dannenberg, Andrew J ; Miller, Meredith A ; Wojnarowicz, Paulina M ; Norton, Larry ; Stoller, Glenn ; Pavletich, Nikola ; Lasorella, Anna ; Iavarone, Antonio ; Lee, Sang Bae ; Ohnaka, Masayuki ; Chin, Yvette ; Hendrickson, Ronald C ; Garcia-Cao, Marta ; Campochiaro, Peter A ; Ouerfelli, Ouathek ; Garcia Escolano, Marta ; Benezra, Robert ; Chodera, John D ; Chaudhary, Jaideep ; Yang, Guangli ; Chang, Sung-Hee ; Soni, Rajesh Kumar ; Lima E Silva, Raquel ; Albanese, Steven K ; Xu, Sijia ; Shah, Riddhi ; Kulukian, Anita ; Garland, William A ; Desai, Bina ; Kadam, Rashmi ; Goldgur, Yehuda ; Philip, John

Id helix-loop-helix (HLH) proteins (Id1-4) bind E protein bHLH transcription factors, preventing them from forming active transcription complexes that drive changes in cell states. Id proteins are primarily expressed during development to inhibit differentiation, but they become re-expressed in adult tissues in diseases of the vasculature and cancer. We show that the genetic loss of Id1/Id3 reduces ocular neovascularization in mouse models of wet age-related macular degeneration (AMD) and retinopathy of prematurity (ROP). An in silico screen identifies AGX51, a small-molecule Id antagonist. AGX51 inhibits the Id1-E47 interaction, leading to ubiquitin-mediated degradation of Ids, cell growth arrest, and reduced viability. AGX51 is well-tolerated in mice and phenocopies the genetic loss of Id expression in AMD and ROP models by inhibiting retinal neovascularization. Thus, AGX51 is a first-in-class compound that antagonizes an interaction formerly considered undruggable and that may have utility in the management of multiple diseases.

npj Breast CancerQ1 · MEDICINE

Anti-tumor effects of an ID antagonist with no observed acquired resistance

Q1 · MEDICINE

ArticleOA

Author: Xu, Sijia ; Rajasekhar, Vinagolu K ; Iavarone, Antonio ; Massague, Joan ; Wojnarowicz, Paulina M ; Hendrickson, Ronald C ; Rosen, Neal ; Yadav, Saurabh ; Zhou, Xi Kathy ; Zhuang, Yuan ; Montrose, David C ; Ouerfelli, Ouathek ; Ratiu, Jeremy ; Healey, John H ; Philip, John ; Soni, Rajesh Kumar ; Yaklichkin, Sergey ; Norton, Larry ; Desai, Bina ; Dannenberg, Andrew J ; Lasorella, Anna ; Chin, Yvette ; Benezra, Robert ; Shah, Riddhi ; Huang, Yun-Han ; Escolano, Marta Garcia ; Garland, William A

AbstractID proteins are helix-loop-helix (HLH) transcriptional regulators frequently overexpressed in cancer. ID proteins inhibit basic-HLH transcription factors often blocking differentiation and sustaining proliferation. A small-molecule, AGX51, targets ID proteins for degradation and impairs ocular neovascularization in mouse models. Here we show that AGX51 treatment of cancer cell lines impairs cell growth and viability that results from an increase in reactive oxygen species (ROS) production upon ID degradation. In mouse models, AGX51 treatment suppresses breast cancer colonization in the lung, regresses the growth of paclitaxel-resistant breast tumors when combined with paclitaxel and reduces tumor burden in sporadic colorectal neoplasia. Furthermore, in cells and mice, we fail to observe acquired resistance to AGX51 likely the result of the inability to mutate the binding pocket without loss of ID function and efficient degradation of the ID proteins. Thus, AGX51 is a first-in-class compound that antagonizes ID proteins, shows strong anti-tumor effects and may be further developed for the management of multiple cancers.

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Indication	Highest Phase	Country/Location	Organization	Date
Neoplasms	Preclinical	US	AngioGenex, Inc.	-

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