Molecular glue degraders offer to significantly expand the druggable genome through their ability to target proteins with no ligand binding sites. Thalidomide analogs offer a case-study in molecular glue mechanisms, with the discovery of neosubstrate degrons enabling prospective searches for on- and off-target activities. Structure-based approaches to molecular glue drug discovery show promise for the rational identification and optimization of novel glue systems, generating a unique and differentiated target space.

This talk will discuss Plexium's latest approaches to discovering novel molecular glues and monovalent degraders of therapeutically important cancer targets. It will highlight Plexium's unique approach and capabilities to discover monovalent degraders and expand the E3 ligase toolbox.

CK1a, an isoform of casein kinase 1 (CK1), promotes tumor growth by increasing the negative effects of MDM2 and MDMX on p53. This presentation will discuss our efforts to identify cereblon (CRBN) E3 ligase-mediated CK1a-selective molecular glue degraders, which demonstrated good PK properties and robust pharmacological activities in various preclinical models of AML.

Proteolysis-targeting chimera (PROTAC) is a frequently used approach for targeted protein degradation. In this talk, we’ll present development and application of high throughput technologies to quantitatively measure absolute protein abundance for target protein and E3 ligases, and determine degradation kinetics of PROTACs in cells. Case studies will be included to demonstrate their impact on compound profiling and differentiation for PROTAC projects.

Small molecules that induce protein degradation through ligase-mediated ubiquitination, are showing considerable promise as a new pharmacological modality. Following clinical proof of concept by thalidomide and related IMiDs, several new molecular entities are entering clinical development. Significant progress has been made towards chemically induced targeted protein degradation using heterobifunctional small molecule ligands and exciting opportunities arise from better understanding molecular glues. We will present recent work towards a better understanding of the molecular principles that govern neo-substrate recruitment by small molecule degraders.

I will present our recent progresses for the development of degraders for both intracellular and extracellular proteins. For the former, I will focus on the development of rapid synthesis of PRTAC (Rapid-TAC) platforms. For the latter, I will focus on the development of degraders that recruit different lysosome targeting receptors.

Targeted protein degradation by small molecules have shown consolidated promise as a new pharmacological approach. We give an overview of our lead generation cascades for the protein degradation modality with focus on proteomics strategies to define degraders selectivity and mechanism of actions. We discuss assay toolboxes and future direction of unbiased discovery of emerging molecular glue degraders and relationship between target and ligase to inform design.

This talk will describe the design, SAR and in vitro/vivo properties of Phenyl Glutarimide (PG) and Phenyl Dihydrouracil (PD) ligands, and corresponding BET, JAK and LCK PROTACs. Comparative studies with corresponding IMiD PROTACs, and screening efforts for alternative CRBN binders will also be discussed.    

Activating point mutations and chromosomal fusions of the Rearranged During Transfection (RET) receptor tyrosine kinase drive numerous human cancers. Here we describe the medicinal chemistry efforts leading to the orally bioavailable, pan-mutant, and pan-fusion RET heterobifunctional degrader, compound 9. In vitro, compound 9 promotes potent degradation of the wild-type and mutant RET kinase domains. In vivo, oral dosing of compound 9 in xenograft models of RET-driven cancers leads to robust tumor regression.

While targeted protein degradation therapies hold much promise, the challenges of achieving the right balance of potency, exposure, and tolerability represent hurdles to development. Herein we present the rationale, implementation, and progression of first-in-class, dual precision targeted protein degrader (TPD²). We developed a proprietary class of GSPT1 degrader molecules and paired them with a Her2 targeting antibody, then we profiled these conjugates for the desired therapeutic profile. Our first clinical GSPT1 TPD² conjugate; ORM-5029 demonstrated superior in vitro and in vivo potency as compared to other known small molecule GSPT1 degraders as well as other ADC's in Her2 models including those with low-Her2 settings.

Targeted Protein Degradation has the potential to transform the treatment of disease. C4T’s TORPEDO platform enables the design of potent, selective, and orally available targeted protein degraders including monofunctional or MonoDAC degraders and heterobifunctional or BiDAC degraders and has delivered a robust pipeline of preclinical candidates. The presentation will discuss in vitro and in vivo strategies and challenges in the context of degrader drug discovery. As a case study, preclinical ADME properties of CFT8634, a potent, selective, and orally available BiDAC degrader of BRD9 for the treatment of SMARCB1-perturbed cancers will be discussed.

A platform to accelerate optimization of proteolysis targeting chimeras (PROTACs) has been developed using a direct-to-biology (D2B) approach focusing on linker effects. A large number of linker analogs, with varying length, polarity, and rigidity, were rapidly prepared and, without chromatographic purification, characterized in four cell-based assays by streamlining time-consuming steps in synthesis and purification. The expansive dataset informs on linker structure-activity relationships (SAR) for in-cell E3 ligase target engagement, degradation, permeability, and cell toxicity.

A significant drawback of PROTACs is their large size, which will likely limit bioavailability, especially to the CNS and in solid tumors. Here we show that rapidly reversible bio orthogonal reactions can be employed to assemble active PROTACs inside of cells from their component target protein and E3 Ub ligase ligands. These much smaller pieces may exhibit superior bioavailability and in vivo efficacy for some applications.

Synovial sarcoma is a rare, often aggressive malignancy with limited therapeutic options. In preclinical studies, FHD-609 has been shown to selectively degrade bromodomain-containing protein 9 (BRD9), taking advantage of a synthetic lethal relationship with the SS18-SSX translocation. The discovery and optimization of this first-in-class clinical compound will be described.