Medicines targeting STING are intensely pursued as innate immune modulators with potential to complement other immuno-oncology agents. While the first wave of STING agonists are derived from cyclic dinucleotides limited to intra-tumoral delivery, we discovered a small molecule dimeric ligand known as the ABZI series that is selective STING agonists with remarkable single agent efficacy upon intravenous delivery.

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.

The CETSA® HT assay offers a robust label-free method for studying protein−compound interactions in a cellular environment. Welcome to learn about the CETSA HT methodology and principles for drug profiling including generation of relevant structure-activity relationship (SAR) data, screening and hit confirmation.

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).

New combination strategies are needed to increase therapeutic efficacy of anti-PD-1/PD-L1-based immunotherapy. Autophagy is associated with a proinflammatory response regulating innate immunity. We found that genetic and pharmacological inhibition of the novel autophagy target Vps34 reduce tumor growth and increase the infiltration of immune cells with cytotoxic activity. Furthermore, treatment with small molecule Vps34 inhibitors (whose discovery is described in a presentation on ‘FBDD’ track) significantly improved the efficacy of anti-PD-L1/anti-PD1 therapy.

Fibrosis accounts for approximately 45% of all deaths in the industrialized world. Galectin 3 are associated with the pathology of fibrosis in different organs such as lung and liver. We have discovered and taken two novel small molecule galectin 3 inhibitors to clinic GB0139 (Phase 2b) and GB1211(Phase 1). This lecture will describe the discovery and development of GB1211, the first orally available galectin inhibitor taken into clinical studies.

Pharmaceutical research teams increasingly rely on SciFinder-n, the most advanced research solution in the SciFinder family, to help them improve productivity, inspire innovation and feel confident in advancing their projects and programs forward.  This talk will demonstrate, with practical examples, how SciFinder-n helps solve problems in small molecule drug  discovery.

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) have the potential to 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.

At SyntheX, we have developed a novel approach to drug discovery by using synthetic biology to create cell-based drug discovery engines for challenging targets; ToRPPIDO is focused on protein-protein interaction (PPI) disruption and ToRNeDO is focused on discovering novel molecular degraders of proteins. Both technologies rely on functional first-pass selections to identify rare molecules that can perform complex intracellular functions. We aim to expand the drug discovery toolkit to enable access to targets that have been previously deemed 'undruggable'. We couple our intracellular selections with genetically-encoded libraries of peptides and macrocycles to generate molecular probes from a first pass screen. These initial molecules can then be used to discover biological insights such as new binding pockets and allosteric sites, or be turned into drugs using medicinal chemistry approaches.  

Using ToRPPIDO, we developed STX100, a peptide originating from an encoded library, targeting an intracellular protein-protein interaction in the homologous recombination DNA repair pathway. STX100-mediated cell killing is independent of canonical cell death mechanisms; it relies on acute calcium release from its target to elicit cell death. The mechanism translates to in vivo models, where a local delivery of STX100 and a combination of immune checkpoint blockade (ICB) agents can cure established tumors resistant to ICB therapies.