Abstract B007: Potent antitumor activity of a novel and orally available small-molecule antagonist targeting the CD47/SIRPα pathway
Immune Modulators(2018)
Abstract
Abstract Antibodies targeting PD-1 and PD-L1 towards stimulation of T cells have revolutionized cancer therapy because of the highly durable response in multiple cancer indications. Although macrophages and other myeloid immune cells offer much promise as effectors of cancer immunotherapy, efforts to modulate them for therapeutic benefit have gained momentum only in the last few years. The CD47/signal regulatory protein alpha (SIRPα) axis is a critical regulator of myeloid cell activation and serves as an immune checkpoint for macrophage-mediated phagocytosis. Because of its frequent upregulation in several cancers, CD47 contributes to immune evasion and cancer progression. Disruption of CD47-SIRPα interaction is now being evaluated as a therapeutic strategy for cancer with the use of monoclonal antibodies targeting CD47 or SIRPα, and engineered receptor decoys. In view of the requirement for the intravenous dosing for all reported CD47 targeting agents, we sought to discover and develop an orally available small-molecule CD47 antagonist. An oral CD47 agent potentially offers the convenience, flexibility to adjust the dose and schedule to address any emergent adverse events, and ease of combination therapy. Through rational design based on the crystal structure of CD47/SIRPα interacting interface, we generated a series of peptides capable of disrupting CD47-SIRPα interactions. Relative binding affinities of the peptides were determined in a newly established cellular assay that utilizes a SIRPα-derived peptide as the probe. The high-affinity peptides were further truncated to identify the shortest peptide pharmacophore. The elements of this pharmacophore were incorporated into nonpeptidic small-molecule scaffolds, resulting in lead compounds disrupting CD47/SIRPα interaction. The lead CD47 antagonists induced phagocytototic activity of human macrophages to a similar extent as commercially available anti-CD47 antibodies. Further optimization of these leads resulted in compounds with desirable physicochemical properties and good oral bioavailability. An advanced lead CD47 antagonist inhibited primary tumor growth (~90%TGI) in a mouse syngeneic model of B-cell lymphoma upon twice-a-day oral dosing. Biomarker characterization and efficacy studies in additional tumor models are ongoing. These findings support further development of these orally bioavailable agents for use in the clinic. Citation Format: Pottayil G. Sasikumar, Chennakrishnareddy Gundala, Wesley R. Balasubramanian, Sudarshan S. Naremaddepalli, Archana Bhumireddy, Sandeep S. Patil, Amit A. Dhudashiya, Vijaysai Rayavarapu, Anirudha Lakshminarasimhan, Dodheri S. Samiulla, Kiran Aithal, Girish Daginakatte, Murali Ramachandra. Potent antitumor activity of a novel and orally available small-molecule antagonist targeting the CD47/SIRPα pathway [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr B007.
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Key words
Cancer Immunotherapy,CD47,Immune Regulation,Tumor Targeting
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