PARP1 inhibitors are effective therapies for BRCA-deficient cancers but cause toxicity due to their lack of specificity for the DNA-damaged active form of PARP1. The discovery that HPF1 forms a composite active site with PARP1 and mediates its activity during the DDR presents an excellent therapeutic opportunity. My project aims to develop next-generation inhibitors that selectively target the PARP1-HPF1 complex.
I have biochemically screened >200 compounds, identifying initial hits with varied selectivity and potency profiles. I will utilize SeeSAR to bridge the gap between this experimental data and structural understanding, elucidating the precise SAR driving inhibition and PARP1-HPF1 selectivity. These structural insights will guide the design of novel scaffolds, which I will use to search the vast chemical spaces available through infiniSee and infiniSee xREAL. This iterative test-analyze-design workflow aims to evolve our current mM hits into potent, pM selective inhibitors.
Luis Enrique intends to achieve the following milestones:
- Elucidate the structural basis of PARP1-HPF1 selective inhibition with SeeSAR.
- Pharmacophore-driven discovery of new comounds with infiniSee and infiniSee xREAL.
- Lead optmization with SeeSAR toward pico-molar potent inhibitors and experimental validation.