Small molecule ubiquitin ligase modulators for immunotherapy of cancer

Abstract An exciting and promising new avenue for cancer treatment is the inhibition of immune evasion the employment by tumors of various strategies to suppress the host immune system s ability to recognize and destroy cancer cells Immunotherapies including monoclonal antibodies transplanted stem cells and engineered T cells vaccines cytokines and T cell checkpoint blockers have shown efficacy against hematologic and solid tumors Owing to the complexity of immune evasion however combination protocols will likely be needed for optimal therapeutic management Side effects associated with current immunotherapies including severe autoimmune disease also support development of alternative immuno oncology agents Thus there is much interest among biotech and pharmaceutical organizations and academic laboratories to find small molecules that promote anti tumor immunity A promising new target is Cbl b a RING finger E ubiquitin ligase expressed primarily in immune cells and critical to immune suppression in the form of T Cell anergy induced by TGF and regulatory T cells Treg Cbl b ubiquitylates the p subunit of PI K disrupting its recruitment to CD in T cells and has an inhibitory role in regulating NK cell functions via TAM receptor kinases Cbl b mice reject various implanted tumors and significantly delay outgrowth of spontaneous tumors either knocking out Cbl b or inhibiting TAM kinases leads to NK cell mediated rejection of metastases Antitumor activity of Cbl b mice is attributed to hyperactivated CD T cells and NK cells Thus Cbl b is a well validated immuno oncology target and Cbl b inhibitors are expected to decrease p ubiquitylation and TAM receptor kinases promoting T and NK cell activation In an HTS campaign using a homogenous TR FRET based Tyro substrate ubiquitylation assay Progenra discovered novel selective Cbl b inhibitors and demonstrated efficacy in various cellular models including primary T and NK cells It is proposed here to conduct hit to lead optimization of Cbl b inhibitors and evaluate them in biochemical cellular and genetic models of T and NK cell activation In particular Cbl b inhibitors are expected to decrease ubiquitylation of substrates Tyro and p increase cytokine production e g IL and IFN and activate T and NK cells Selective Cbl b inhibitors demonstrating cellular and in vivo proof of concept will enter pre clinical development in Phase II chemical optimization ADME in vivo efficacy as clinical candidates for novel immuno oncology therapies Promising new cancer therapies work by blocking the tumor s ability to escape detection and killing by cells of the patient s immune system Some of these drugs are active but do not block all of the tumors evasion mechanisms and or produce severe side effects so new immunosuppressing cancer drugs are needed This proposal describes the discovery of a new class of immuno oncology drug inhibitors of a ubiquitinating enzyme associated with blocking the ability of immune cells to eradicate tumors