Abstract 5552: Novel, heterocyclic small molecule inhibitors of PD-1 and PD-L1 pathway

The PD-1/PD-L1 molecular pathway is one of the primary mechanisms of immune evasion deployed by cancer cells. Induction of PD-L1 expression on cancer cells is associated with inhibition of immune responses against cancer, thus permitting cancer progression and metastasis. Activation of PD-1/PD-L1 pathway induces apoptosis of activated T-cells, inhibits their proliferation, facilitates T-cell anergy and exhaustion and enhances the function of regulator T-cells. Therefore, blocking this pathway restores the proliferation and cytotoxicity of CTLs, inhibits the function of Tregs and results in decreased T-cell apoptosis. A number of cancer immunotherapy agents targeting PD-1/PD-L1 have been developed and approved for a number of malignancies (PD-1: Nivolumab, Pembrolizumab, PD-L1: Atezolizumab, Avelumab, Durvalumab). However, there is a still a need for potent, selective small molecule inhibitors of the PD-1/PD-L1 pathway. The approved therapies require bolus intravenous injections, are administered in high dose and have a long half life. The long residence time of these mAbs could contribute to the well-documented drug-related adverse effects. Small molecule inhibitors, therefore, can provide increased oral bioavailability, increased bio-efficiency and shorted half life activity for a more controllable treatment, particular in the case of auto-immune or other adverse effects. Rational and structure guided de novo design approaches were used to design novel small molecule PD-1/PD-L1 pathway inhibitors; potency of these inhibitors was assessed in an in-vitro TR-FRET assay. Checkpoints signaling reporter assays as well as ex-vivo co-culture assays were used to assess the ability of the compounds to restore T-cell proliferation and function. Three novel chemical series as potent PD-1/PD-L1 pathway inhibitors are being developed for the treatment of cancer. Compounds from these series showed strong in vitro potency of 0.01 to 0.2 µM against PD-1/PD-L1. JBI-426 exhibited an IC50 of 0.04 µM and no cytotoxicity against cancer cell proliferation per se. JBI-426 showed good in vitro ADME properties in terms of aqueous solubility, metabolic stability, permeability and excellent oral bioavailability in mouse pharmacokinetics. In a RENCA syngeneic model, oral administration of JBI-426 at 50 mg/kg resulted in a strong tumor growth inhibition, comparable (or better) than the PD-L1 mAb, and was well tolerated. The effect of JBI-426 on tumor infiltrating lymphocytes was also