Highly Specific ATR Inhibitors: Targeted Therapy for a Broad Specturm of Cancers
Laura R. Butler1*, Ryan L. Ragland2*, Hank J. Breslin1, Tina Gill1, Eric J. Brown2**, and Oren Gilad1**
1Atrin Pharmaceuticals, Doylestown, Pennsylvania; 2Abramson Family Cancer Research Institute and the Department of Cancer Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA. *, **Equal contributions
Ataxia Telangiectasia and Rad3-related (ATR) and Checkpoint Kinase 1 (CHK1) stabilize stalled replication forks and prevent their collapse into DNA double strand breaks (DSBs). Combining ATR suppression with over-expression of HRASG12V, KRASG12D or MYC synergistically increases the formation of DSBs and causes synthetic lethality1,2. These findings define a genetic context and level of ATR pathway inhibition in which a broad variety of cancers displaying oncogenic stress can be targeted with minimal impact on normal tissue homeostasis.
We have recently developed and tested a novel series of small molecules that inhibit ATR kinase activity in the low nanomolar range in cell culture. This series exhibits exquisite selectivity for ATR with 800-fold lower inhibitory activity towards other DNA-damage activated PIK-related kinases. ATR inhibition by these compounds causes DSB formation during S-phase and suppresses aphidicolin-induced CHK1 S345 phosphorylation to basal levels at concentrations that are approximately 50-fold lower than other clinically applied ATR inhibitors. ADME profiling indicates that these compounds are stable in vivo. Preliminary data suggest these compounds are able to selectively promote lethality in cells expressing HRASG12V or over-expressing MYC, while leaving wild-type unstressed cells relatively unaffected. In addition, single-dose examination of one ATR inhibitor (ATRN-119) indicates that the growth of many NCI 60 cell lines is substantially limited by ATR inhibition.
Many standard-of-care chemotherapies operate through abrogating DNA synthesis. However, these strategies, while effective, have undesirable side effects due to their ability to affect the proliferation of normal cells as much as cancer cells. The specificity of ATR pathway inhibition enables directed killing of replicating cells experiencing oncogenic stress. This targeted approach suggests that Atrin’s highly specific ATR inhibitors will efficiently limit the progression of a wide variety of cancers with decreased side toxicities.
1. Schoppy DW, Ragland RL, Gilad O, Shastri N, Peters AA, Murga M, Fernandez-Capetillo O, Diehl JA, Brown EJ: Oncogenic stress sensitizes murine cancers to hypomorphic suppression of ATR. Journal of Clinical Investigation 122(1): 241-252, 2012.
2. Gilad, O., Nabet, B.L., Ragland, R.L., Schoppy, D.W., Smith, K.D., Durham, A.C., Brown, E.J.: Combining ATR suppression with oncogenic Ras synergystically increases genomic instability, causing synthetic lethality or tumorigenesis in a dosage-dependent manner. Cancer Research 70(23): 9693-9702, 2010.