Novel G9a inhibitor cancer therapy
The potential of epigenetic modifying drugs to address difficult-to-treat cancers and therapy resistance positions them as the potential next wave of cancer therapy blockbusters.
Collaborative research between QIMR Berghofer (led by Professor Frank Gannon and Dr Jason Lee) and Domainex, a UK-based medicinal chemistry CRO, has identified a series of novel epigenetic modifying molecules which inhibit the G9a enzyme. G9a inhibition changes the nature of the cancer cells, ‘unmasking’ cancer cells to the immune system, shutting off the mechanism of therapy resistance, and driving cell-death pathways.
Initially using a tool molecule inhibitor of G9a (G9ai), we have shown efficacy of the target in multiple cancer types, including melanoma, breast, ovarian, and pancreatic cancers. G9a inhibition has demonstrated efficacy as a monotherapy, and when used in combination with standard of care treatments such as chemotherapy or endocrine therapy. In combination, G9a inhibition increases the sensitivity and/or reversed therapy resistance, producing synergistic benefits.
The current lead development compound, identified from the chemistry series of Domainex, demonstrates superior efficacy in mouse models of melanoma (with the remainders ongoing), and with a single round of optimization has already achieved multiple desired parameters of the TPP. Further, there are three alternative molecules from the lead series, and two back-up chemistry series of different chemotypes within the program, that have also shown G9a inhibition. Unlike the tool compound used for the proof of concept studies, the novel Domainex molecules have favorable drug-like molecular and physical properties, as well as good manufacturability profiles.
To enable further structure activity relationship based optimization, we have an established in vitro screening cascade of robust and sensitive assays. These assays were validated and used for assessing the discovery series molecules from Domainex, and successfully identified the current lead candidates from within the lead series.
We are seeking capital investment to enable a new company vehicle to develop our novel G9a inhibitor from the current lead molecule through to a Phase I-ready compound.