Discovery of TREX1 Antagonists for Cancer Immunotherapy - Summary
TREX1, the major cytosolic exonuclease, plays an important role in preventing aberrant immune
responses to self-DNA in normal cells. However, multiple lines of evidence indicate that TREX1 dampens the
intrinsic immune response to tumors by preventing activation of the DNA-sensing cGAS/STING pathway in tumor
cells, which is required for activation of T cells and cross presentation of tumor antigens by dendritic cells.
Moreover, TREX1 expression is upregulated by DNA damaging treatments that are being investigated as ‘in situ
vaccines’ to improve responses to existing immune checkpoint inhibitors; e.g., radiotherapy in combination with
PD-1 blockers.
We are proposing to develop small molecule inhibitors of TREX1 for
cancer immunotherapy. In Phase I, we will lay the groundwork for a
successful TREX1 lead discovery program incorporating both high throughput
screening (HTS) and virtual screening (VS). We will develop a robust, HTS-
compatible enzymatic assay for TREX1, which will serve as the primary
biochemical tool for discovering inhibitors and developing them into lead
molecules, and perform a pilot screen with a 20K diversity library to validate
the assay. We will also use advanced computational methods to develop a
pharmacophore model for the TREX1 active site and perform a virtual screen
of lead like molecules, which will be assessed with the HTS assay.
Successful completion of these aims will put us in a strong position to pursue
a full scale TREX1 lead development program in Phase II, powered by the
proven preclinical discovery platform that we have assembled for the related
target cGAS, under separate SBIR grants. To our knowledge, there are no
small molecule TREX1 inhibitors; using both HTS and VS will maximize the
Type I IFNs
TREX1 acts as a checkpoint on antitumor
immunity by preventing activation of the
cGAS/STING pathway by cytosolic DNA.
chemical space that we can sample, an important consideration for an unexplored target, both from a scientific
and intellectual property perspective.
The potential medical impact of TREX1 blocking drugs is broad and fundamental, as they could potentially
be used to improve responses to existing checkpoint blockers, all of which act downstream; to allow lower dosing
of cytotoxic therapies; or as monotherapy to stimulate a T cell response in immunogenically ‘cold’ tumors.
