CDC7 Kinase Inhibitor Combination Therapy to Treat Cancer

Background

Many small-molecule CDC7 inhibitors have been developed as the focus of multiple drug discovery programs in oncology as an alternative strategy to restrain DNA replication in cancer.

There are a number of CDC7 kinase inhibitors in development as an anti-cancer treatment and many are in clinical trial. However, problems persist in this approach where there are ongoing issues with reaching a good level of efficacy whilst avoiding toxicity of these CDC7 kinase inhibitors. In particular, dose-limiting tolerability issues have been observed with some inhibitors leading to their clinical trial termination.

Thus, there is an unmet need for improving the efficacy and tolerability of CDC7 kinase inhibitors.

Technology Overview

To understand how the problems in DNA replication arising from CDC7 inhibition are dealt with we performed a genome-wide CRISPR/Cas9 chemogenetic screen to identify genes, that upon loss, could sensitize to the anti-proliferative effects of CDC7 inhibitors. Top hits were rigorously validated alone and in combination with CDC7 inhibitors.

Despite the typical monotherapeutic approach for treatment of cancer, we found for the first time that CDC7 inhibition together with the inhibition of the top hit from the CRISPR/Cas9 screen synergises in stopping DNA replication and cell proliferation. Therefore, the combination therapy using CDC7 inhibitors with inhibitors of the top hit from the CRISPR/Cas9 screen can be more efficacious and less toxic than CDC7 inhibitor monotherapy for the treatment of solid cancers, blood cancers and other proliferative diseases. Data shows that this combination approach increases antiproliferative activity of CDC7 by about 10‑fold.

Benefits

• Unmet medical need for improved potency and efficacy of CDC7 kinase inhibitors with an increased therapeutic window
• Lower cytotoxic effects
• Ability to target aggressive cancers such as colorectal, pancreatic and lung
• Scientifically validated
• Patent protected

Applications

• Therapeutics

Opportunity

• Licensing
• Collaboration