Rapid progress has been made advancing novel TPD therapies in recent years, highlighting their huge clinical potential but also identifying opportunities where further enhancements can increase their impact further. This presentation will reflect on where there is the biggest opportunity for next-generation TPD approaches to achieve clinical impact and Amphista's own progress in identifying new degrading mechanisms and warheads which are directly expanding the potential of the TPD field.

Degradation of pathogenic protein represents an important new modality in drug discovery. Here we describe the discovery of novel monovalent protein degraders and molecular glues using Plexium's approach. These monovalent degraders extend the options for targeted protein degradation beyond bivalent degraders and cereblon IMIDs.

Targeted protein degradation (TPD) is an emerging therapeutic modality with promise across diverse diseases.  In the ~20 years since the idea of using bifunctional small molecules that recruit ubiquitin ligases to induce target degradation, 10+ TPD drug candidates have entered clinical trials, spawning a mini-biotech industry based on molecules that induce ‘proximity’ to impact target biology. Arvinas is a pioneer in the field and continues pushing the boundaries of TPD. This presentation will highlight recent developments in the Arvinas PROTAC Discovery Engine, focusing on the mechanistic and structural basis of small molecule degrader discovery highlighting recruitment of new ubiquitin ligases.

This presentation highlights C4T’s platform build to enable rational and efficient discovery of Monofunctional Degradation Activating Compounds (MonoDACs) through the design and evolution of a diverse chemical library combined with various screening approaches. Leveraging this platform, we will discuss a snapshot of the key SAR advancements leading to the discovery of IKZF1/3 degrader, CFT7455, currently in clinical development, as well as the identification of the first MonoDAC hit to a novel therapeutic target.

Targeted protein degradation technologies including the degradation tag (dTAG) system have emerged as powerful approaches to control protein abundance using small molecule degraders. This talk will describe the development and recent advances of the dTAG technology platform and will highlight case studies demonstrating utility for preclinical target discovery and validation in refractory cancers.

Receptor-interacting protein kinase 1 (RIPK1) is a master regulator of cell fate and controls proinflammatory signaling downstream of multiple innate immune pathways. Leveraging the Proteolysis targeting chimera (PROTAC) technology, we developed a first-in-class RIPK1 degrader, which sensitizes ICBs by not only overcoming the intrinsic resistance in cancer cells but also activating a B cell subpopulation to contribute to antitumor immunity.

Casitas B-lineage lymphoma b (CBL-B) is an E3 ligase that functions as a negative regulator of T, NK, and myeloid cells. Mice deficient in CBL-B reject tumors in syngeneic models, suggesting that inhibition of CBL-B may be a novel therapeutic strategy. We present discovery and optimization of compounds including NRX-8 (KD=20nM) that glue CBL-B into an inactive conformation. NRX-8 increases T cell activation in response to TCR stimulation and inhibits tumor growth in syngeneic models of cancer when dosed orally. We present preclinical data on NX-1607, a more potent CBL-B inhibitor being evaluated in a Phase I trial in multiple oncology indications.

Formation of ternary complexes between a ligase, a molecular glue, and a disease-modulating protein is the first step in a sequence of events leading to protein degradation.  In this presentation, we discuss the SPR and X-ray crystallographic characterization of ternary complexes involving a molecular glue that binds to the ligase Cereblon and induces the binding of the zinc finger-containing transcription factor IKZF2.

Targeted protein degradation of disease-causing proteins is a promising new therapeutic modality. Established protein degradation technologies using PROTACs or molecular glues utilize the ubiquitin proteasome system to degrade intracellular proteins.  A novel approach has emerged for extracellular protein degradation that utilizes the asialoglycoprotein receptor (ASGPR) to recruit pathogenic proteins for endolysosomal degradation. We describe the discovery of novel bifunctional compounds called ATACs (ASGPR-Targeting Chimeras) containing Avilar’s proprietary, high affinity, small-molecule ASGPR-binding ligands.

Development and validation of high-specificity nanobodies for intracellular targeting remain a bottleneck. Here we describe a yeast surface display based nanobody screening approach that led to high specificity nanobodies against several intracellular targets in parallel. We also present a comprehensive comparison of nanobody-ubiquitin ligase F-box fusions for targeted degradation of intracellular proteins. Using these approaches, we demonstrate robust degradation of the RNA-binding protein HNRNPA2B1, implicated in multiple cancers and neurodegenerative diseases.

TPD² approach merges the power of targeted protein degraders with the precision of antibodies to deliver molecular glues or PROTACs intracellularly with cell-specificity, overcomes many of the challenges of small molecule degraders, and increases the therapeutic index of degraders. Using the TPD² approach, the Antibody neoDegrader Conjugate (AnDC) platform has been developed using highly specific GSPT1 degraders that show promising efficacy against hematological malignancies and solid tumors. Two AnDCs in clinical/late preclinical testing, ORM-5029 for breast cancer and ORM-6151 for AML will be discussed. Furthermore, a second TPD² platform PROTAB used to deliver hetero-bifunctional PROTACs will also be highlighted.