Here, I will give an overview of Amgen's Induced Proximity Platform with a focus on our Targeted Protein Degradation effort. I will review new approaches to characterize novel E3 ubiquitin ligases for development of PROTACs and/or molecular GLUEs. Finally, I'll highlight our progress in the discovery of new chemical ligands for ligases previously not developed for Targeted Protein Degradation.

Immunomodulatory Drugs (IMiDs) and IMiD-based PROTACs rapidly hydrolyze in commonly utilized cell media, which can significantly affect their cell efficacy. This talk will describe the design of novel CRBN binders with improved ligand efficiency and chemical stability. Their application in the design of potent and selective PROTACs directed to oncoproteins such as BRD4, JAK2 and LCK will also be discussed.

Eurofins Discovery has developed a novel cell-based platform, SPRINTer Cell Lines, for the functional assay of protein degraders and is currently diversifying for new disease targets. Here, we present validation data of degraders that target BRD4 and its downstream c-MYC.  In addition, introduce the new SPRINTer cell lines that aim to identify degraders for BTK and IKZF1 and modulators for CDKN1A (p21) in mid to high TP homogenous format.  

Cancer cells that are insensitive to apoptosis usually evade killing mediated by the antitumor immunity. We developed a novel PROTAC that can synergize with anti-PD1 to trigger immunogenic cell death and significantly inhibit tumor growth in syngeneic mouse tumor models.

We report the discovery of small-molecule degraders, HB007, of the small ubiquitin-related modifier 1 (SUMO1). Using diverse biochemical assays, we identified the binding protein as cytoplasmic activation/proliferation-associated protein 1 (CAPRIN1) and the substrate receptor as F-box protein 42 (FBXO42). Upon binding, HB007 induced the interaction of CAPRIN1 with FBXO42 recruiting SUMO1 to the CAPRIN1-CUL1-FBXO42 UB ligase complex where SUMO1 was ubiquitinated. HB007 degraded SUMO1 in patient-derived xenografts reducing cancer progression.

This talk will provide an overview of the discovery and advancement of FHD-609, Foghorn Therapeutics’ novel protein degrader currently in clinical trials for the treatment of synovial sarcoma. FHD-609 is a potent, selective, intravenously administered protein degrader of BRD9, a component of the ncBAF complex. In preclinical studies, FHD-609 has demonstrated tumor growth inhibition in synovial sarcoma, a cancer that is genetically dependent on BRD9.

Microfluidic Diffusional Sizing (MDS) is an emerging technology for in-solution characterization of protein interactions. MDS was recently applied to studying and characterizing the interaction of Brd4-BD2 and VCB complex as mediated by the PROTAC molecule MZ1. The collected data supports analysis of the binding parameters of the ternary system, including the KD values for both binary interactions as well as the cooperativity factor using a simple workflow.

The unique MOA of PROTACs provides promising opportunities in the discovery and development of innovative therapeutics. Synthesis and optimization of PROTACs via traditional iterative synthesis for any drug discovery program can be very time-consuming. We have developed a highly efficient High-Throughput Chemistry Direct-to-Biology platform to conduct miniaturized reactions in 1536-well plates to make a large set of PROTACs and directly assess these crude reactions in a cellular degradation assay. Case studies will be presented to showcase how the platform can impact timelines for identifying new PROTACs.

The ubiquitin proteosome system consists of a diverse array of potential therapeutic targets. To date, many of these remain “undruggable." A major challenge is the lack of a versatile platform that can be broadly used to interrogate structure-function relationships. We use protein engineering to overcome this hurdle. Our ubiquitin variants can specifically inhibit or activate a myriad of UPS enzymes, which can then be used to identify drug leads.

Monte Rosa’s QuEEN (Quantitative and Engineered Elimination of Neosubstrates) platform enables us to rationally design selective molecular glue degraders (MGDs). To connect MGDs to degrons, we use a tailored Glueomics toolbox of biochemical, biophysical, structural biology, cellular, proteomics, and in silico screening tools. Here we will discuss how we utilize a biochemical and biophysical understanding of the ternary complex in the discovery of MGDs that selectively degrade therapeutically relevant but previously undruggable or inadequately drugged proteins.

This talk will cover the development of a mechanistic mathematical model for the use of irreversible covalent chemistry in targeted protein degradation (TPD), either to the target protein of interest (POI) or E3 ligase ligand, considering the thermodynamic and kinetic factors governing ternary complex formation, ubiquitination, and degradation through the UPS. Insights highlighting the key advantages of covalent E3 PROTACs to engage and degrade target proteins and increase catalytic efficiency in TPD will be presented. Covalent binding to the target can also confer limited benefits, to overcome weak target binding resulting in a boost in ternary complex concentration that can promote degradation but under 1:1 PROTAC:target stoichiometric conditions. Effects of intrinsic values of E3 ligase and target turnover on degradation efficacy, and the relationship of fractional E3 occupancy and degradation will also be explored.

Protein degradation is a novel modality with the potential to tackle therapeutically interesting proteins previously seen as undruggable. In this area, CETSA is a powerful technology for identifying binders, investigating target engagement and the mechanism of action of the protein degraders – in intact living cells. We will show how CETSA can be applied in various stages of drug discovery to provide data that is both actionable and biologically relevant.

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.

Molecular glue degraders have astonishing pharmacological properties. However, their discovery had been mostly driven by serendipity. Differential chemical profiling using specific mutants enables scalable target-agnostic identification of molecular glues.

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.