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

NPJ Breast Cancer. 2021 May 24;7(1):58. doi: 10.1038/s41523-021-00266-0.

Paulina M Wojnarowicz ¹, Marta Garcia Escolano ¹, Yun-Han Huang ¹ ² ³, Bina Desai ¹, Yvette Chin ¹, Riddhi Shah ¹, Sijia Xu ¹, Saurabh Yadav ¹, Sergey Yaklichkin ¹, Ouathek Ouerfelli ⁴, Rajesh Kumar Soni ⁵, John Philip ⁵, David C Montrose ⁶ ⁷, John H Healey ⁸, Vinagolu K Rajasekhar ⁹, William A Garland ¹⁰, Jeremy Ratiu ¹¹, Yuan Zhuang ¹¹, Larry Norton ¹², Neal Rosen ¹³, Ronald C Hendrickson ⁵, Xi Kathy Zhou ¹⁴, Antonio Iavarone ¹⁵, Joan Massague ¹, Andrew J Dannenberg ⁶, Anna Lasorella ¹⁶, Robert Benezra ¹⁷

Affiliations

1 Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
2 Weill Cornell/Sloan Kettering/Rockefeller Tri-Institutional MD-PhD Program, New York, NY, 10065, USA.
3 Gerstner Sloan Kettering Graduate School of Biomedical Sciences, New York, NY, 10065, USA.
4 Organic Synthesis Core Facility, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
5 Proteomics & Microchemistry Core Facility, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
6 Department of Medicine, Weill Cornell Medical College, New York, NY, USA.
7 Department of Pathology, Renaissance School of Medicine, Stony Brook University, Stony Brook, NY, USA.
8 Orthopedics Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
9 Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
10 Tosk, Inc., Mountain View, CA, USA.
11 Department of Immunology, Duke University, Durham, NC, USA.
12 Evelyn H. Lauder Breast Center, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
13 Molecular Pharmacology Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
14 Department of Healthcare Policy and Research Weill Cornell Medical College, New York, NY, USA.
15 Department of Neurology, Department of Pathology, Institute for Cancer Genetics, Columbia University Medical Center, New York, NY, USA.
16 Department of Pediatrics, Department of Pathology, Institute for Cancer Genetics, Columbia University Medical Center, New York, NY, USA.
17 Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA. [email protected].

PMID: 34031428 DOI: 10.1038/s41523-021-00266-0

Abstract

ID 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.

Products

Cat. No.

Product Name

Description

Target

Research Area
HY-129241

AGX51

99.09%, Pan-Id Antagonist

Others

Cancer

Name
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