TM serine/threonine kinase (ATM) is a serine/threonine-protein kinase and can be recruited and activated by DNA double-strand breaks. Specifically, ATM phosphorylates several key proteins. These proteins initiate the activation of DNA damage checkpoints, leading to cell cycle arrest, DNA repair, or apoptosis. Besides, ATM belongs to the superfamily of phosphatidylinositol 3 kinase-associated kinases (PIKKs). This protein kinase family includes ATR (ATM- and RAD3-related), DNA-PKcs, and mTOR. Moreover, ATM-mediated DNA damage includes rapid response and delayed response. Protein kinase ATM may also participate in mitochondrial homeostasis. Furthermore, it acts as a regulator of mitochondrial autophagy, thus eliminating the dysfunction of ancient mitochondria.
ATM and ATR also interact with many proteins that are Co-located at the site of DNA damage. Meanwhile, ATR can also bind to Rad17 and BRCA1 and is relevant to the components of the nucleosome remodeling and deacetylation (NRD) complexes. Nonetheless, ATM and ATR have shown phosphorylation of p53 protein in serine 15 to enhance its activation activity. Importantly, ATR responds to a wide range of DNA damage, including DSB and damage caused by interference with DNA replication and increased replication pressure. Here, we will introduce an orally available and selective ATR inhibitor, Elimusertib.
Elimusertib is an Orally Available and Selective ATR Inhibitor.
First of all, Elimusertib (BAY 1895344) is a potent, orally available, and selective ATR inhibitor with an IC50 of 7 nM. Particularly, Elimusertib potently inhibits the proliferation of a broad spectrum of human tumor cell lines with a median IC50 of 78 nM. Obviously, Elimusertib potently suppresses hydroxyurea-induced H2AX phosphorylation (IC50=36 nM).
In the second place, Elimusertib has a very promising effect in the monotherapy of DNA damage deficient tumor model and the combination therapy with DNA damage induction therapy. Additionally, Elimusertib exhibits strong anti-tumor efficacy in monotherapy in a variety of xenograft models of different indications with DDR deficiencies. In the xenograft model of bone metastasis of CRPC, the combination of Elimusertib and Radium-223 showed significant synergistic antitumor activity.
All in all, Elimusertib is a potent, orally available, and selective ATR inhibitor.
References:
Ulrich T. Luecking, et al. Cancer Research. July 2017 Volume 77, Issue 13 Supplement.