Novel, brain penetrant small molecule inhibitor of PD-L1 for targeting glioblastoma and brain metastasis

Background: The PD-1/PD-L1 molecular pathway is one of the primary mechanisms immune evasion deployed by cancer cells and anti-PD-L1 monoclonal antibodies (mAbs) restore T-cell proliferation enhanced tumor cell killing which has been shown to result in clinically revolutionary efficacy many types. Unfortunately, this not case CNS tumors where these mAbs have failed show improved responses survival. It appears that main reasons for poor brain penetrance clinical evidence suggests increasing results better efficacy. Therefore, small molecule inhibitors PD-L1 with could become highly valuable therapy. In addition, molecules optimized oral bioavailability short half-life, can address other known limitations antibodies, including well-known immune-breakthrough toxicities. JBI-2174 an orally available selective inhibitor similar binding mechanism action as antibodies. penetrant shows comparable approved preclinical studies. Materials methods: Structure based drug design was used inhibitors; potency assessed in-vitro TR-FRET assay. Reporter assays ex-vivo co-culture were assess function. Pharmacokinetics performed multiple pre-clinical species derive at penetration. vivo mice syngeneic orthotopic models. Results: Our lead showed strong vitro IC50 1.5 nM assay measures interaction between PD-1 also induced dimerization This augmented response measured IFN-g activation a cell-PBMC Competition study blocking antibody x-ray co-crystallization studies clearly demonstrate finger-print on More importantly, good across sustained exposure (0.66 2.1 fold plasma vs. ratio). Atezolizumab hPD-L1/MC38 models administration. Toxicological conducted non-human primates well tolerated exposures much higher than efficacious exposure. Conclusion: Oral administration provides attractive option be treatment glioblastoma solid metastasis. IND-enabling are being initiated compound. No conflict interest.