Abstract 5552: Novel, heterocyclic small molecule inhibitors of PD-1 and PD-L1 pathway
Authors: Dhanalakshmi Sivanandhan , Garapaty Shivani , Venkateshappa Chandregowda , Seerapu Guru Pavan , Das Reshma , Nagaraj Pradeep , Kar Ronodip , Singh Anuj Kumar , Venkatesubbiah Venkatesha Ashokkumar , Putta Ramakishore VP , Pendyala Muralidhar , Lokesh Girisha , Madaka Hari , Thummuru Harikrishna Reddy , AP Shikas , Anchan Prateeksha , Bhat Prathima , G Rudresha , Zainuddin Mohd , V Krishnakumar , Gosu Ramachandraiah , Kristam Rajendra , DA Jeyaraj , Rajagopal Sriram 
Published: August 2018

Abstract
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 assessed; a significant increase in CD8+ cytotoxic lymphocytes was observed. Further studies to assess additional compounds from the three chemical series are underway. The oral administration route of these PD-1/PD-L1 inhibitors would provide an attractive alternate to the currently available antibodies in treating cancer either as a stand-alone therapy or in combination with other immuno-modulatory agents, as well as other standard of care agents.
Citation Format: Sivanandhan Dhanalakshmi, Shivani Garapaty, Chandregowda Venkateshappa, Guru Pavan Seerapu, Reshma Das, Pradeep Nagaraj, Ronodip Kar, Anuj Kumar Singh, Venkatesha Ashokkumar Venkatesubbiah, Ramakishore VP Putta, Muralidhar Pendyala, Girisha Lokesh, Hari Madaka, Harikrishna Reddy Thummuru, Shikas AP, Prateeksha Anchan, Prathima Bhat, Rudresha G, Mohd Zainuddin, Krishnakumar V, Ramachandraiah Gosu, Rajendra Kristam, Jeyaraj DA, Sriram Rajagopal. Novel, heterocyclic small molecule inhibitors of PD-1 and PD-L1 pathway [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5552.