Progress towards a clinically-successful ATR inhibitor for cancer therapy

Abstract

The DNA damage response (DDR) is now known to play an important role in both cancer development and its treatment. Targeting proteins such as ATR (Ataxia telangiectasia mutated and Rad3-related) kinase, a major regulator of DDR, has demonstrated significant therapeutic potential in cancer treatment, with ATR inhibitors having shown anti-tumour activity not just as monotherapies, but also in potentiating the effects of conventional chemotherapy, radiotherapy, and immunotherapy. This review focuses on the biology of ATR, its functional role in cancer development and treatment, and the rationale behind inhibition of this target as a therapeutic approach, including evaluation of the progress and current status of development of potent and specific ATR inhibitors that have emerged in recent decades. The current applications of these inhibitors both in preclinical and clinical studies either as single agents or in combinations with chemotherapy, radiotherapy and immunotherapy are also extensively discussed. This review concludes with some insights into the various concerns raised or observed with ATR inhibition in both the preclinical and clinical settings, with some suggested solutions.

Keywords: ATM; ATR; ATR inhibitors; Chemo- and radiosensitisers; DDR.

Graphical abstract

Fig. 1

DDR and cancer development. The presence of DNA damage either by exogenous or endogenous agents triggers the functional mechanisms of DDR leading to the rapid and efficient repair of DNA damage through cell cycle arrest and delays, and in some cases, apoptosis of cells when DNA damages accumulate beyond repair. This maintains genomic integrity which is critical for cell survival and viability. In contrast, DDR dysfunctions, which may be due to mutations and/or dysregulation of DDR mechanisms, can lead to inefficient or unrepaired DNA damage that in turn destabilise the genome of these cells. Genomic instability induces various aberrant cellular behaviours leading to the development of cancers.

Fig. 2

Schematic diagram of the domain structure of ATM and ATR. Known structural domains are shown for each protein; FRAP–ATM–TRRAP domain (FAT), FAT C-terminal domain (FATC), Phosphatidylinositol 3-kinase-related kinase domain (PIKK), Tel1/ATM N-terminal motif (TAN), ATR interacting protein (ATRIP), and UVSB PI3 kinase, MEI-41 and ESR1 domain (UME). ATM and ATR consist of 3656 and 2644 amino acids respectively. (Adapted from Weber and Ryan, 2015).

Fig. 3

The signalling cascades of ATM and ATR. ATM and ATR activate their distinct key mediator, CHK2 and CHK1 respectively, in response to respective DNA damage, and through various downstream substrates (p53, BRAC, Cdc25A, Cdc25c), which are commonly shared among these kinases, execute their respective functions to maintain the genomic integrity of cells. ATR and ATM may interconvert depending on the cellular content and the type of DNA damage to compensate for one another.

Fig. 4

Chemical structures of caffeine and wortmannin, which are among the early agents used in ATR inhibition studies.

Fig. 5

Chemical structures of reported ATR inhibitors in preclinical development.

Fig. 6

The chemical structures of ATR inhibitors currently being evaluated in Phase I & II cancer clinical trials.