Protagonist Therapeutics is pioneering a potential first-in-class oral peptide targeting the IL-17 pathway. While current treatments rely on injectable biologics, our program demonstrates the unique therapeutic potential of an orally delivered peptide that inhibits both IL-17A and IL-17F. The key takeaways are: (1) Modality shift: The unique advantages of oral peptides over traditional biologic injections. (2) Comprehensive targeting: Why simultaneously blocking both IL-17A and IL-17F is critical for optimal efficacy. (3)  Patient impact: How oral delivery can transform treatment algorithms and improve compliance in chronic inflammatory diseases.?

Biologics targeting cytokines have transformed immunology but remain limited by injection, immunogenicity, and cost, motivating oral small-molecule alternatives. The discovery of such molecules has been slow and inefficient, primarily because early hits often lack direct functional readouts and mechanistic prioritization. We present a function-first lead generation workflow using the OdyssION platform, integrating native MS and HDX-MS. Native MS provides quantitative affinity and stoichiometry during primary screening, enabling selection of defined binding modes. HDX-MS then captures mechanism-linked conformational signatures to prioritise functional, allosteric hits. Applied to TNFa, this approach offers a generalisable blueprint for discovering oral cytokine inhibitors.

Genetic evidence links CARD9 to IBD risk, but a rare protective variant highlights its potential as a therapeutic target. We utilized a “binder-first” discovery strategy as a steppingstone for this challenging scaffolding protein. This approach ultimately yielded potent inhibitors that successfully suppress CARD9-mediated inflammatory signaling in vitro and in vivo, validating a new pharmacological strategy for treating immune-mediated inflammatory diseases.

STAT6 is an attractive target for immune diseases such as asthma and COPD in addition to AD and certain lymphoma. We present development of exceptionally potent, selective, and orally active STAT6 degraders based upon allosteric small-molecule inhibitors of STAT6.

STAT6 is the transcription factor downstream of IL-4/IL-13 signaling, with IL-13 playing a key role in atopic dermatitis. In this talk, we report the first disclosure of a series of STAT6 PROTACs as a potential oral therapy for type II inflammatory diseases. Combining Almirall’s selective STAT6 binders with diverse linkers and VHL ligands resulted in potent, selective PROTACs. Further optimization of their physicochemical properties led to orally bioavailable, subnanomolar PROTACs.

The discovery and characterization of EPS-3903, a novel STAT6 inhibitor, will be presented. EPS-3903 demonstrates nanomolar potency across multiple cell types and has shown in vivo efficacy comparable to dupilumab in preclinical models. Moreover, EPS-3903 displays optimized pharmacokinetic properties with excellent target tissue penetration. The favorable profile of EPS-3903 suggests its potential as a best-in-class oral STAT6 inhibitor with once-daily dosing in humans for the treatment of allergic diseases.

We engineered a balanced, long-acting unimolecular triagonist simultaneously targeting FGF21, GLP-1, and GIP receptors. Through strategic N- and C-terminal modifications and lipid conjugation, we first optimized FGF21 alone to achieve enhanced potency, stability, and sustained pharmacokinetics. Then, we engineered the GLP1R, GIPR and FGF21R triagonist achieving near-normalization of body weight with significant reductions in body fat and improved glucose tolerance, positioning it as a next-generation metabolic disease therapy.

GPR61 is a brain-enriched class A orphan GPCR that may be involved in appetite and body-weight modulation. Herein we describe our medicinal-chemistry efforts in discovering a class of potent, selective, and brain-penetrant GPR61 inverse agonists from an HTS hit. Cryo-EM structures reveal this class of inverse agonists binds to an induced intracellular allosteric pocket and abolishes GPR61 activity by disrupting its interactions with G protein.

Oral small-molecule GLP-1 agonists with engineered signaling bias could deliver injectable-level metabolic efficacy with reduced side effects. Conventional approaches treat the receptor as a static cryo-EM snapshot, producing leads that bind without achieving desired signaling profiles. DEEP DISCOVERY (US Patent Nos. 12,450,409 and 12,424,300) learns structure-function correlation across the GPCR superfamily by telescopically integrating structural, ligand, and functional data, then uses CAM-guided saliency to infer receptor conformations biased toward a specified signaling state and generates ligands designed to stabilize it. Here, Gs-coupled over beta-arrestin. We present our GLP-1 lead, designed for oral bioavailability, and the path to preclinical validation.

Targeting KRAS remains challenging due to its dynamic signaling and rapid emergence of resistance to Switch-II pocket inhibitors. I will present structural insights into how KRAS conformational dynamics shape effector engagement and pathway output. I will also discuss how recurrent resistance mutations remodel the Switch-II pocket by weakening key drug interactions or by occluding the binding site while preserving oncogenic signaling. These findings provide a framework for understanding resistance and guiding next-generation therapies.

PP2A is a Ser/Thr phosphatase that regulates the phosphorylation of virtually all cellular processes. Despite its importance, mechanisms that regulate its turnover is poorly understood. Here, we find that the E3 ligase SCFFBXO42 degrades PP2A in complex with the coiled-coil protein CCDC6 to maintain cancer cell fitness. The cryoEM structure of this complex reveals a template-driven mechanism mediated by CCDC6 and represents a new mode of E3:substrate recogntion.

This presentation describes the discovery of PLN-101095, a dual avß8/avß1 integrin inhibitor that blocks TGF-ß activation in the tumor microenvironment. It highlights the integrin chemistry and biology expertise underlying the program, the rationale for dual targeting, and translational data supporting clinical development. Preliminary Phase 1 data will be presented, including pharmacodynamic changes during a 14-day monotherapy lead-in, with increases in plasma IFN-ɣ and PD-L1 expression observed in the responders.

The Glucocorticoid-Induced TNF Receptor (GITR) modulates both innate and adaptive immune responses. As antibody-based agonists have faced limitations, we engineered a small molecule, KROS-101, through a structure-based approach. KROS-101 expanded effector T cells and downregulated immunosuppressive Treg cells, with potent anti-tumor activity as a single agent in syngeneic colon tumor models. Further clinical development as a next-generation checkpoint agonist for first-in-man studies are forthcoming.

DNA-damage response (DDR) proteins are prime targets in combinatorial cancer therapies and cases of synthetic lethality. We discover and develop novel target-specific DDR therapeutics targeting multiple DDR proteins, including small molecule inhibitors and targeted protein degraders dependent on fragment- and structure-based drug discovery. Our approach reveals locations and poses of ligands and details of protein-ligand interactions, target ligandability, orthosteric, and potential allosteric sites, allowing rapid assessment of synthetic tractability and intellectual property.

Targeted protein degradation (TPD) of Leucine rich repat kinase 2 (LRRK2) offers an exciting opportunity to drug this Parkinson's disease relevant protein. Here we describe a two-pronged approach to optimize LRRK2-VHL PROTACs for in vivo application. First, we optimized an SPR system to look at LRRK2-VHL ternary complexes and identify potent LRRK2 PROTACs before optimizing the DMPK of these LRRK2 degraders. Secondly, we have used a direct-to-biology (D2B) approach to rapidly identify new chemical matter than can degrade LRRK2. This talk demonstrates the advancement in LRRK2 VHL PROTACs towards an in vivo active PROTAC.

Leucine-rich repeat kinase 2 (LRRK2) regulates cellular processes including endo-lysosomal function, autophagy, and neuroinflammation. Elevated LRRK2 activity and expression are linked to familial and sporadic Parkinson’s disease and implicated in progressive supranuclear palsy (PSP). We developed LRRK2 PROTAC degraders as potential disease-modifying therapies. Here, we highlight optimized degraders that are potent, orally bioavailable, blood-brain barrier penetrant, and capable of reaching deep brain regions impacted by neurological disease.

Economic burden of neurodegenerative diseases exceeded trillions of dollars in 2025. Recently launched biologicals provide marginal benefit. Parkinson’s and Alzheimer’s diseases (PD/AD) are driven by protein aggregation—such as a-synuclein and tau—that disrupts mitochondrial function. Damaged mitochondrial kinase PINK1 phosphorylate ubiquitin activates parkin ligase to promote mitophagy and autophagy. A potent PINK1/Parkin molecular-glue drug to remove protein aggregates and damaged mitochondria and restore mitobiogenesis will be discussed.

TMEM175 is a K and H channel that regulates lysosomal pH and a-synuclein degradation. Studies indicate that TMEM175 gain-of-function protects against PD progression. In this study, we developed high-throughput FLIPR and electrophysiological assays to screen for novel TMEM175 activators. We characterized potential hits by developing a world-first high-throughput lysosomal patch-clamp assay to determine on target potency. We also validated hits effects on native lysosomal pH in human neural progenitor cells.

TREM2 (Triggering Receptor Expressed on Myeloid Cells 2) loss-of-function variants are strongly associated with AD. TREM2 deficiency in preclinical models causes excessive neuronal loss and memory impairment, while therapeutic TREM2 activation reduces Aß plaques and improves memory deficits. TREM2 agonists are currently in clinical development for early AD. We developed a human iPSC-derived tri-culture system to investigate TREM2 activation. Transcriptomic analysis showed that TREM2 small molecule agonist partially reversed disease-associated signatures from patient samples and attenuated inflammatory responses in vivo. The tri-culture system demonstrated reduced astrogliosis and inflammatory cytokine production following TREM2 agonist exposure, supporting its therapeutic potential under inflammatory conditions both in vitro and in vivo.

Bruton’s tyrosine kinase (BTK), a Tec-family non-receptor tyrosine kinase, is required for antigen-specific BCR signaling and Fc-gamma receptor signaling in monocytic cells. In multiple sclerosis (MS), CNS B-cell pathways in meningeal ectopic follicles and Fc-gamma-mediated microglial pathways are thought to drive disease pathogenesis and progression. BTK inhibition is therefore expected to reduce MS-related immune inflammation. This presentation describes our strategy to identify a brain-penetrant, covalent BTK inhibitor with the potency, selectivity, and pharmacokinetic properties needed for rapid systemic and CNS inactivation. Supported by in vivo efficacy, favorable tolerability, and PET-confirmed brain target engagement, BMS-986196 advanced to clinical studies.

Lysosomal dysfunction and alpha-synuclein aggregation drive Parkinson's disease (PD) onset and progression. A human iPSC tri-culture system of neurons, microglia, and astrocytes was developed to explore how lysosomal alterations influence neuroinflammation and neurodegeneration. Following a-synuclein pre-formed fibril treatment, these disease-relevant models showed robust pathway alterations and dysregulated neuronal function, suggesting lysosomal defects are upstream drivers of PD pathology. This platform enables evaluation of therapeutics targeting lysosomal restoration for drug development.