AZD7762, a novel checkpoint kinase inhibitor, drives checkpoint abrogation and potentiates DNA-targeted therapies

Abstract

Insights from cell cycle research have led to the hypothesis that tumors may be selectively sensitized to DNA-damaging agents resulting in improved antitumor activity and a wider therapeutic margin. The theory relies on the observation that the majority of tumors are deficient in the G 1 -DNA damage checkpoint pathway resulting in reliance on S and G 2 checkpoints for DNA repair and cell survival. The S and G 2 checkpoints are regulated by checkpoint kinase 1, a serine/threonine kinase that is activated in response to DNA damage; thus, inhibition of checkpoint kinase 1 signaling impairs DNA repair and increases tumor cell death. Normal tissues, however, have a functioning G 1 checkpoint signaling pathway allowing for DNA repair and cell survival. Here, we describe the preclinical profile of AZD7762, a potent ATP-competitive checkpoint kinase inhibitor in clinical trials. AZD7762 has been profiled extensively in vitro and in vivo in combination with DNA-damaging agents and has been shown to potentiate response in several different settings where inhibition of checkpoint kinase results in the abrogation of DNA damage-induced cell cycle arrest. Dose-dependent potentiation of antitumor activity, when AZD7762 is administered in combination with DNAdamaging agents, has been observed in multiple xenograft models with several DNA-damaging agents, further supporting the potential of checkpoint kinase inhibitors to enhance the efficacy of both conventional chemotherapy and radiotherapy and increase patient response rates in a variety of settings. [Mol Cancer Ther 2008;7(9):2955 -66]

Checkpoint kinase inhibitor synergizes with DNA‐damaging agents in G1 checkpoint‐defective neuroblastoma

“…The best synergy was found between AZD7762 and gemcitabine, as observed in other tumor systems. 4,5 Although gemcitabine is not yet a standard agent for the treatment of neuroblastoma, 31 our data strongly support the potential of combination therapy with checkpoint kinase inhibitor like AZD7762 and gemcitabine for recurrent tumors and for preventing the emergence of resistant clones.…”

“…AZD7762 has been documented as an equally potent inhibitor of both Chk1 and Chk2 in vitro. 5 However, recent studies suggested that potentiation effects on DNA-damaging agents were driven primarily via inhibiting Chk1 rather than Chk2. Moreover, addition of Chk2 inhibition failed to enhance cell kill when compared to using only Chk1 inhibition (reviewed in Ref.…”

“…The Chk1/2 inhibitor, AZD7762 [3- 5 was kindly provided by AstraZeneca R&D (Boston, MA). Cisplatin, doxorubicin (Adriamycin) and etoposide were obtained from Bedford Laboratories (Bedford, OH); gemcitabine (Gemzar) from Eli Lilly (Indianapolis, IN); vincristine (Vincasar) from SICOR Pharmaceuticals (Irvine, CA); topotecan (Hycamtin) from GlaxoSmithKline (Research Triangle Park, NC); SN38 (the active metabolite of irinotecan) from Abatra Technology (Xi'an, China); and melphalan from Sigma.…”

“…4 Recently, a novel and specific Chk1/2 inhibitor, AZD7762, was shown to potentiate the effect of DNA damaging agents in carcinomas derived from the breast, cervix, colon and lung. 5 What is not known is whether AZD7762 can also act as a potentiating agent in the treatment of embryonal tumors, such as neuroblastoma, retinoblastoma, high risk sarcoma and brain tumors with known aberrations in the G 1 checkpoint (p53 and Rb mutations) or p53 pathway defects.…”

Manipulating DNA damage-response signaling for the treatment of immune-mediated diseases

“…Additionally, a recent report that T cells down-regulate p53 upon TCR stimulation also suggested to us that T cells may rely strongly on the S and G 2 /M checkpoints (17). To test this hypothesis we used two different inhibitors of S and G 2 /M cell cycle checkpoint proteins: the WEE1 inhibitor (WEE1 i ) AZD1775 (23) and the CHK1/2 inhibitor (CHK i ) AZD7762 (24). Although the two compounds have distinct targets, they ultimately function by promoting premature S or G 2 /M progression and initiation of mitosis.…”