With both T cells and NK cells dependent on arginine, arginase has been recognized as a major immune-suppressive mechanism. We developed a small molecule arginase inhibitor that demonstrates in vivo activity evidenced by an increase in plasma and tumor arginine levels, reactivation of anti-tumor immunity, and single agent anti-tumor activity. Combination with various immune activators, including checkpoint inhibitors, further increases signs of immune activation as well as anti-tumor response.

Function of the mitochondrial enzyme F1Fo-ATPsynthase is compromised in both acute and chronic pathologies. This makes the enzyme an exploitable target to devise innovative therapeutics for long-term metabolic dysfunctions such as cancer. In my talk, I shall illustrate our progresses on this account by reporting synthesis and in vitro characterisation of the NH-Sulfoximine (NHS) which exploits the bio-energy dependent on mitochondria acting in reverse to deliver cytostatic effect.

Despite clinical progress in a broad range of tumor types with immune checkpoint inhibitors, many patients don’t respond to therapies. The talk will focus on a CRISPR/Cas9 mediated in vivo screen platform enabling identification of genes that control cancer cell sensitivity to T cell-mediated elimination as potential targets or biomarkers.

Indoleamine 2,3-dioxogenase-1 (IDO1) is induced and activated in response to viral and bacterial infection causing a dysfunctional immune response in clearing pathogens. IDO1 inhibitors (IDO1i) can potentially restore immune function in indications such as cancer and infection. A structurally-unique IDO1i class was discovered through the affinity selection of a novel DNA-encoded library. After additional medicinal chemistry iterations, the compound series was elaborated into potential best in class preclinical molecule.

RIP1 kinase is a critical mediator of multiple signaling pathways that regulate inflammatory responses and cell death. Using RIP1 kinase inhibitor, GNE684, we show that RIP1 inhibition can efficiently block arthritis, skin and liver inflammation, and colitis in animal disease models. Conversely, RIP1 inhibition had no effect on tumor growth, metastases or viral infections. Together these data emphasize the protective role for RIP1 kinase inhibition in inflammatory disease.

Post-translational functionalization of most secreted and transmembrane proteins requires co-translational translocation to the ER through Sec61. Translocation is negotiated by protein interactions between Sec61 and unique signal sequences specific to each translating protein. Disruption of these interactions in specific or multi-signal sequence fashion presents an opportunity to modulate protein homeostasis toward therapeutic benefit. Development of signal and multi-signal sequence selective Sec61 inhibitors as novel anti-cancer agents will be discussed.

Macrophages can adopt different functional roles in response to signals from their environment, including the ability to direct pro-inflammatory and anti-inflammatory immune responses. Verseau is utilizing its proprietary all human drug discovery and translation platform to develop an expansive pipeline of macrophage checkpoint modulators. At Verseau we have nominated and validated more than two dozen targets that modulate human macrophage biology. The lead program targeting PSGL-1, reprograms macrophages to a pro-inflammatory state, activates T cells and attracts other immune cells to generate a coordinated and powerful anti-tumor response.

Covid-19 has been declared a global pandemic by WHO. There are hundreds of active clinical programs focused on developing and repurposing therapeutic drugs for treatment of Covid-19. In this talk, we highlight how our cell-based assays are supporting these programs, particularly in managing proinflammatory cytokines associated with high mortality rate in Covid-19 patients.

IL-36 cytokines, pro-inflammatory members of the IL-1 superfamily, are upregulated in inflammatory disorders. Targeting IL-36 signaling has been an attractive approach for several dermatological diseases including psoriasis. I will present our discovery of A-552, a novel first in class small molecule antagonist of the IL-36 signaling pathway. A-552 binds potently and selectively to human IL-36g and was capable of attenuating IL-36g induced responses in mouse and human disease models.

Covalent modification of BTK has been proven to be beneficial for cancer patients with multiple drugs on market while their safety profiles are concerned for autoimmune disease indications. A reversible non-covalent BTK inhibitor will have the promise to address this unmet need. We will report our discovery of BIIB068, an exquisitely selective, potent, reversible BTK inhibitor, together with the med chem strategy and Phase I clinical results.

This presentation will cover the discovery and development of AUR101, an ROR-gamma inverse agonist. AUR101 is currently in Phase 2 clinical trials for the treatment of psoriasis (ClinicalTrials.gov Identifier: NCT04207801).