The av integrins (avb1, avb3, avb5, avb6, avb8) are a subset of a family of heterodimeric transmembrane proteins that mediate cell-cell and cell-extracellular matrix signaling. I will discuss the role of integrins in immuno-oncology and will describe the development of our integrin inhibitor library. I will also present the challenges in targeting integrins with small molecule drugs.

Small molecule agents targeting immune checkpoint receptors or ligands may offer advantages in cancer therapy, and a demonstration of their clinical utility is awaited from the ongoing trials. Interestingly, emerging data support the involvement of several targets, generally considered as oncogenic growth drivers, in immune modulation. Progress at Aurigene in the discovery of small molecule agents targeting CD47, PRMT5 and KAT6A and their impact on anti-tumor immunity will be presented.

SyntheX developed STX100, a stabilized peptide, to target an intracellular PPI within the homologous recombination (HR) DNA repair pathway. Using this compound, we have discovered a novel immunogenic cell death mechanism that exploits the overexpression of Rad51 in cancer cells relative to healthy tissues to elicit an acute calcium-dependent cell death. STX100 demonstrates single agent in-vivo efficacy for multiple tumor types and shows remarkable synergy with checkpoint inhibitors.

I present our recently published data on the structure and dynamics of the full-length CD47, a membrane protein receptor against which many biopharma companies are developing 'blockers' for potential use as an IO therapy. The structure reveals that this receptor adopts a novel transmembrane domain fold and highlights the important role of the extracellular loops for immune recognition, signaling, and therapeutics. [Nat Commun 12, 5218 (Sep2021)]

I will discuss a new way to inhibit the programmed death-ligand 1 (PDL1) via small molecules. We induced dimerization and internalization of PDL1 via a small molecule drug candidate. This represents a mechanism of checkpoint inhibition different from anti-PDL1 antibodies which function through molecular disruption of the programmed death 1 interaction.

The Adenosine A2a Receptor (A2aR) has become the target of new investigational therapies for immuno-oncology. Tumors alter their environment in a variety of ways including creating an abundance of extracellular adenosine. Adenosine mediated activation of A2aR on immune cells suppresses immune activity by inhibiting proliferation, maturation, polarization, chemotaxis, and phagocytosis. This presentation will review the biological underpinnings and recent chemical matter targeting A2aR for immuno-oncology.

The CBL-B E3 ubiquitin ligase functions as a negative regulator of T cell receptor activation. We report discovery of NX-1607, an orally bioavailable CBL-B inhibitor that demonstrates anti-tumor activity in multiple preclinical tumor models. NX-1607 triggers rapid NK and T cell infiltration of tumors and shows increased frequency of tumor rejection in combination with anti-PD-1. Our studies provide rationale for clinical development of NX-1607 in advanced malignancies.

The Ral-GEF pathway is one of the three major K-RAS signaling pathways.  Like K-RAS, Ral GTPases are difficult targets, but Rgl2, a Ral guanine exchange factor, has several cysteines on its surface.  We screened a library of cysteine electrophiles and identified chloroacetamide and acrylamide fragments that inhibited Ral GTPase exchange by Rgl2. These allosteric covalent fragment inhibitors provide a starting point for the development of small-molecule covalent inhibitors to inhibit RAS signaling in animal models. This work was published in January 2022 in ChemMedChem.

Potent inhibitors of human purine nucleoside phosphorylase (PNP) were developed and the biological properties of selected candidates were evaluated. Currently, only a single drug (forodesine) based on the PNP inhibition is approved (only in Japan) for the treatment of T-cell acute lymphoblastic leukemias (T-ALLs), but with serious adverse events. Our compounds, similarly to forodesine, have the potential to treat various T-ALLs.

I describe our Conformational Genetics approach to understand the molecular basis of diseases and provide conformational hypotheses for drugging the target. This approach involves mapping disease-driving genetic mutations onto 3-dimensional protein structures, then running a suite of molecular dynamics simulations to determine low-energy conformational states and energetic landscapes. We show examples of Conformational Genetics on cancer and autoimmune targets: NLRP3, SHP2, and PP2a.

The University of California Drug Discovery Consortium (UCDDC) strives to leverage the biomedical research and commercialization strengths of the University of California (UC) system to accelerate the development of life-saving therapies and to translate discoveries into knowledge driven commercial enterprises that stimulate California’s economy. The UCDDC Executive Committee works with each UC-campus to advance drug development by providing expertise in drug discovery and by building relationships between industry and academics.

Injectable biologic mAbs inhibiting the IL-17A pathway have become established as highly effective and safe treatments for moderate to severe psoriasis. An oral therapy, with similar efficacy and safety to these biologics, is desirable and in this presentation; we will disclose the discovery of our 1st small molecule (Rule-of-5 compliant) orally bioavailable clinical candidate that binds to IL-17A to modulate its structure and function.

Bruton’s tyrosine kinase (BTK) inhibitors are actively being explored in inflammatory diseases. However, they are characterized by modest selectivity and/or limited central nervous system (CNS) penetrance. GB7208 is an orally available, selective, irreversible small molecule BTK inhibitor selected based on its potency, specificity, and high brain penetrance in preclinical models. Together, these features differentiate GB7208 from other BTK inhibitors currently under clinical investigation in CNS diseases.

I will discuss quantitative FRET (qFRET) technology development for SUMOylation inhibitor discovery against viruses and cancers. We have developed a series of novel qFRET technologies for high-throughput screenings and drug discoveries for protein-protein interactions and pathway inhibitor discovery. We recently show that SUMOylation inhibitor can completely inhibit influenza viruses and its drug resistant strains. Colleagues have shown that SUMOylation inhibitors have improve efficacy of anti-PD1 and anti-CTLA4 antibody in mice.

Epstein-Barr virus is responsible for 1-2% of all human cancers and is associated with a number of autoimmune diseases, including multiple sclerosis. Latent EBV infection depends on the continuous expression of Epstein-Barr Nuclear Antigen 1 (EBNA1), a multifunctional dimeric protein critical for viral replication, genome maintenance and viral gene expression. We used a fragment-based approach to discover a small molecule lead series that selectively inhibits the DNA-binding activity of EBNA1.  I will describe the structure-based lead optimization that led to the identification of a clinical candidate that is now in phase 2 clinical trials.