Abstract 297: The novel orally available sub-nanomolar potent and selective checkpoint kinase 1 inhibitor CASC-578 is highly active in mantle cell lymphoma as a single agent and in combination with Wee1 inhibition

Abstract

Abstract Background: Checkpoint kinase 1 (Chk1) is a serine/threonine protein kinase that regulates cell division by arresting progression in the S & G2 phases of the cell cycle in response to genotoxic stress. Pharmacological inhibition of Chk1 uncouples the completion of DNA replication from G2/M phase transition in tumor cells that have impaired DNA damage response networks, resulting in DNA damage induction, mitotic catastrophe and cell death. These properties make Chk1 inhibition an attractive therapeutic approach as a single agent, or to enhance the efficacy of other cancer drugs that target DNA damage response pathways. Methods and Results: This report highlights the activity of the orally bioavailable, selective, small molecule Chk1 inhibitor, CASC-578, in multiple mantle cell lymphoma (MCL) models in vitro and in tumor mouse xenograft studies. MCL have the common genetic biomarker t(11;14)(q13;q32), a chromosomal translocation leading to the constitutive expression of the oncogene CCND1 which encodes cyclin D1, a cell cycle-regulating protein. This genotypic characteristic has been observed in the clear majority of patients with MCL in the clinic and may provide a rationale for sensitivity to Chk1 inhibition. Consistent with this idea, CASC-578 demonstrated remarkable potency as a single agent in blocking the proliferation of MCL cell lines in vitro, with an average IC50 of 61 nM. Treatment with CASC-575 as a single agent resulted in the induction of DNA damage, as measured by phosphorylated histone H2AX and activation of apoptosis, as measured by cleaved caspase. In a JEKO-1 xenograft tumor study, CASC-578 as a single agent completely regressed subcutaneously implanted tumors in the majority of mice after oral drug administration using 20 mg/kg daily or when dosed on an intermittent schedule at 25 mg/kg, with minimal effects on body weight. In addition to the observed single agent activity of CASC-578, the combination of CASC-578, and the Wee1 inhibitor AZD-1775, was highly synergistic in MCL cell lines including JEKO-1, REC-1, Z-138 and MAVER-1 in vitro. CASC-578 was also highly potent as a single agent, and in combination with AZD-1775, in blocking the proliferation of a variety of leukemia derived cell lines in vitro. Taken together, these data support the advancement of CASC-578 into clinical development as a potential therapeutic agent for the treatment of MCL, as well as other hematological malignancies. Citation Format: Robert Rosler, Janelle Taylor, Dina Leviten, Teresa Sierra, Ashley Dozier, Kevin Klucher, Rich Boyce, Bob Boyle, Alex Vo, Scott Peterson. The novel orally available sub-nanomolar potent and selective checkpoint kinase 1 inhibitor CASC-578 is highly active in mantle cell lymphoma as a single agent and in combination with Wee1 inhibition [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 297. doi:10.1158/1538-7445.AM2017-297