Targeting proteins for proteasomal degradation is an emerging and transformational therapeutic modality. However, the limited number of E3 ligases recruitable by small molecules constitutes a limitation in terms of scope of degradable targets, resistance profile, and cell type-specific toxicity. Amphista has identified drug-like bifunctional compounds that, independently from the traditional E3 ligases generally used, induce profound, fast and selective degradation of a broad range of clinically relevant targets.

Targeted protein degradation by small molecules has shown consolidated promise as a new pharmacological approach. We give an overview of our lead generation cascades for the protein degradation modality with a focus on proteomics strategies to define degraders' selectivity and mechanism of actions. We will discuss case studies on oncogenes and suppressors of tumorgenesis by targeted degradation of PRC2 complex.

Biodegraders are fusion proteins consisting of a target-binding domain and a truncated E3 ligase.  As such, these intracellular biologics can deplete a protein-of-interest through targeted degradation. Here, I will provide an update on our efforts to advance biodegraders as a biological tool and potential novel therapeutic modality with a focus on mRNA as an approach to achieve intracellular expression in target cells.   

Chemical knock-down of proteins by PROTACs is a paradigm shift in the drug discovery field. Currently, PROTACs based on Cereblon, VHL, HDM2 and cIAPs have been exploited by medicinal chemists to degrade a limited set of therapeutic targets. By focusing on novel ubiquitin ligases, Progenra has discovered entirely new classes of PROTACs with applications in oncology, inflammation, and neuroscience.

I will present our discovery and optimization of PROTAC degraders with the objectives to identify suitable candidate compounds for clinical development. First, I will present our discovery and development of degraders against STAT3 and other STAT members, a class of traditionally difficult-to-drug targets and our extensive in vitro and in vivo evaluations.  Second, I will present our discovery and development of highly potent and orally active PROTAC degraders of androgen receptor, estrogen receptor, and MDM2, among others.

Eurofins Discovery will present how the novel E3scan™ technology has been applied to diverse E3 ligases, including CRBN, VHL, MDM2, MDMX, cIAP1, cIAP2, and XIAP. We will also present how engineered biosensor cell lines employing gene editing with CRISPR/Cas9 and our well-established EFC technology will enable sensitive quantitation of PROTAC-mediated degradation of the target of interest in physiologically relevant cell models using a homogeneous assay format.

Our research focuses on leveraging our ubiquitin-mediated, small molecule-induced protein degradation technology for the treatment of cancer and other diseases. I will present the discovery and evaluation of first-in-class potent and selective degraders of an oncogenic target that inhibited cell growth with low nanomolar IC50 values and demonstrated sustained degradation in xenografted tumor models.

Targeted protein degradation has rapidly gained traction as a promising therapeutic approach. Despite this, relatively little is understood about the factors governing a target's propensity for ubiquitination and degradation by specific E3-ligases, and the influence of chemical and cell type-specific variables on the effects of a given degrader molecule. We employed a chemo-proteomic approach to systematically characterize the factors that influence endogenous kinase degradation in different cellular contexts, profiling a library of well-characterized, diverse kinase degraders using a quantitative global proteomics approach.

This talk outlines the design, physicochemical optimisation, and biological activity of a set of novel PROTACs targeting the JAK family of proximal membrane-bound proteins. JAK PROTACs from two distinct chemotypes were designed, optimising the physicochemical properties for each template to enhance cell permeation. These PROTACs are capable of inducing significant JAK1/JAK2 degradation, demonstrating an extension of the PROTAC methodology to an unprecedented class of protein targets and their mechanisms of action.

The on-target and dose-limiting thrombocytopenia limits the use of BCL-X_L inhibitors, such as ABT263, as safe and effective anticancer agents. To reduce this toxicity, we converted ABT263 into DT2216, a BCL-X_L PROTAC that targets BCL-X_L to VHL for degradation. DT2216 was more potent against cancer cells, but less toxic to platelets than ABT263, because VHL is poorly expressed in platelets. This demonstrates the use of PROTACs to reduce on-target drug toxicities.

With PROTACs progressing rapidly towards therapeutic applications, it is important to understand whether and how resistance to these novel agents may emerge. Using BET-PROTACs as a model system, we demonstrate that resistance to both VHL- and CRBN-based PROTACs was primarily caused by genomic alterations that compromise core components of the relevant E3 ligase complexes. This study reveals a novel resistance mechanism distinct from current targeted therapies and warrants future investigations.