AIT-102 Introduction

AIT-102 is a novel molecule that was selected from a series of analogues of the natural product mithramycin1. Mithramycin was originally isolated from the soil bacterium Streptomyces argillaceus, and first approved as a pharmaceutical agent in 1970.  Though it has been used for the treatment of various cancers, its use was limited due to liver toxicity2, and manufacture of mithramycin for pharmaceutical use was discontinued in 20003.

AIT-102 has been determined to have between 25-40x lower toxicity than mithramycin while demonstrating equal or greater anti-tumor activity against multiple tumor cell lines and tumor xenografts1,4.

AIT-102 and Transcriptional Dysregulation

Key hallmarks of cancer include sustained proliferative signaling, evasion of growth suppressors, activation of metastasis, resistance to cell death and perpetuation of immortality5 – all of which are driven by dysregulation in transcription factors such as MYC, SP1, HIF-1 and AP-1.  This dysregulation leads to transcriptional addiction, or an absolute dependence on continued dysregulation of gene transcription for the cancer’s survival6.

AIT-102 binds the minor groove of DNA at GC-rich regions, interfering with the binding of the aforementioned transcription factors, disrupting transcriptional addiction, and thereby halting the tumor’s growth and survival.

AIT-102 has demonstrated antitumor activity in a range of cancers in vitro, including colorectal cancer, triple negative breast cancer, head and neck cancer, melanoma and others1, 7, 8.  Because of the ability of AIT-102 to disrupt transcriptional dysregulation, a key feature of all tumor types, it holds promise as an anti-tumor agent across a wide range of tumors.

AIT-102 References

1 Núñez, L. E., Nybo, S. E., González-Sabín, J., Pérez, M., Menéndez, N., Braña, A. F., ... & Méndez, C. (2012). A novel mithramycin analogue with high antitumor activity and less toxicity generated by combinatorial biosynthesis. Journal of medicinal chemistry, 55(12), 5813-5825.
2 Osada, N., Kosuge, Y., Ishige, K., & Ito, Y. (2013). Mithramycin, an agent for developing new therapeutic drugs for neurodegenerative diseases. Journal of pharmacological sciences122(4), 251-256.
3 NCATS Inxight Drugs:
Méndez, C., González-Sabín, J., Morís, F., & Salas, J. A. (2015).Expanding the chemical diversity of the antitumoral compound mithramycin by combinatorial biosynthesis and biocatalysis: the quest for mithralogs with improved therapeutic window. Planta Medica, 81(15), 1326-1338.
5 Hanahan, D. and Weinberg, R.A. (2011) Hallmarks of Cancer: The Next Generation.  Cell 144, 646-674.
6 Bradner, J. E., et. al. (2016) Transcriptional Addiction in Cancer.  Cell 168, 629-643.
7 Pandiella, A., et. al. (2015) Antitumoral Activity of the Mithralog EC-8042 in Triple Negative Breast Cancer Linked to Cell Cycle Arrest in G2.  Oncotarget 6(32) 32856-32867.
8 Hermida-Prado, F., et. al. (2019) The SRC Inhibitor Dasatinib Induces Stem Cell-Like Properties in Head and Neck Cancer Cells that are Effectively Counteracted by the Mithralog EC-8042. J Clin Med 8. 1157.