Inhibition of CDC7 with Sgr-2921 in AML Models Results in Enhanced DNA Damage and Anti-Leukemic Activity As Monotherapy and in Combination with Standard of Care Agents

Abstract

Introduction: CDC7 is a protein kinase that is active during the S-phase of the cell cycle. CDC7 plays a critical role in the replication stress response by phosphorylation and activation of the BRCA1 and Cohesin complexes, which protect and restart stalled replication forks. In addition, by maintaining DNA helicase activity during replication fork stalling, CDC7 establishes a platform for ATR checkpoint activation. Acute myeloid leukemia (AML) is typically a rapidly proliferating cancer and is characterized by high replication stress and DNA damage. Agents that target replication stress and DNA damage response pathways represent novel therapeutic opportunities in AML. Here we show that inhibition of CDC7 in AML models results in potent anti-tumor activity by amplifying replication stress and DNA damage. We show that CDC7 inhibition has synergistic anti-proliferative effects when combined with hypomethylating agents and a BCL2 inhibitor. We previously discovered that CDC7 activity drives resistance to FLT3 inhibition (Cancer Cell. 2021 Jul 12;39(7):999-1014.e8), and now show that inhibition of CDC7 overcomes resistance to a variety of FLT3 inhibitor resistant cell lines. CDC7 inhibition is efficacious in multiple AML models resistant to standard of care agents, suggesting that CDC7 inhibitor combinations may be efficacious in the clinic. Results: We identified a potent and selective CDC7 inhibitor, SGR-2921, using large-scale physics-based computational modeling technology. In a panel of ~300 cancer cell lines, AML cell lines were on average the most sensitive to SGR-2921, and AML patient samples were highly sensitive to CDC7 inhibition ex vivo. In vivo, SGR-2921 showed strong anti-tumor growth activity in MV-4-11 and Molm-16 AML xenograft models at tolerated doses. In combination with hypomethylating agents, SGR-2921 increased the level of replication stress, DNA damage and apoptosis markers in vitro. Combination of SGR-2921 with venetoclax (BCL2 inhibitor) showed synergy on anti-tumor activity both in vitro and in vivo. SGR-2921 was highly efficacious in AML cell lines resistant to FLT3 inhibitors, hypomethylating agents and venetoclax, and in multi-agent resistant cell lines. Co-treatment with SGR-2921 partially restored sensitivity to FLT3 inhibition in FLT3 resistance AML cell lines. Conclusions: SGR-2921, a novel, potent CDC7 small molecule inhibitor, demonstrates strong anti-proliferative activity both in vitro in AML cell models and in vivo in AML xenograft models. SGR-2921 showed synergistic inhibitory effects on cell-proliferation and tumor growth in combination with standard of care agents, and was anti-proliferative in AML cell lines and patient samples resistant to standard of care agents. Together, these data show that SGR-2921-mediated CDC7 inhibition is an attractive novel treatment opportunity in AML, with a potential utility in patients with relapsed and refractory AML.