The discovery of CC-99282, a CELMoD® agent, was designed to address the needs of patients with relapsed or refractory (RR) lymphomas, who often face poor prognosis and limited life expectancy. This discovery was guided by phenotypic data from diffuse large B-cell lymphoma cells and protein degradation data. CC-99282 promotes an interaction between zinc finger protein neosubstrates like IKZF1/3 (Ikaros/Aiolos) and ZFP91 with cereblon, leading to proteasome-mediated degradation of neosubstrates. This process is associated with clinical activity in various hematologic malignancies, including RR lymphomas.

CREB binding protein (CBP) and E1A binding protein (EP300) are paralog histone acetyltransferases that act as transcriptional co-activators. Dysregulation of one or both proteins has been implicated in various cancers, and functional genomic screens have demonstrated a bidirectional synthetic lethal relationship between these genes in tumor cells. This talk will describe our progress in optimizing heterobifunctional degraders that are highly selective for each of these highly homologous proteins.

Targeted protein degradation using proteolysis targeting chimeras (PROTACs) is a promising therapeutic strategy for the treatment of cancer. However, conventional PROTAC approach has a key limitation– it cannot target a protein of interest which lacks a small-molecule ligand. We developed “Bridged PROTAC” which is a novel protein complex degrader strategy that exploits the target protein’s binding partner to degrade undruggable proteins by inducing proximity to an E3 ubiquitin ligase.

Proteolysis targeting chimera (PROTAC) protein degraders are heterobifunctional small molecules that recruit a protein of interest to an E3 ubiquitin ligase, leading to proteasomal degradation of the target protein. This presentation will: 1) provide a brief overview of the PROTAC technology; 2) discuss physicochemical property guidelines for attaining oral absorption in the beyond-rule-of-5 space occupied by PROTAC degraders.

We have developed a proprietary platform technology, RaPPIDS (Rapid Protein Proteolysis Inducer Discovery System), with highly productive synthesis and evaluation, leading a drug candidate of IRAK-M degrader, FIM-001. The platform has been continuously improved and extended to identify novel E3 ligase binders by taking a phenotypic-first approach. This is an innovative strategy to select a suitable E3 ligase for a protein of interest and the discovery of novel PROTAC degraders.

Targeted protein degradation separates from other drug discovery modalities by its catalytic mechanism to achieve high efficacy, the ability to target previously undruggable proteins, and its potential to deliver drug activity to selective tissues. All three features depend on the E3 ligands, which are currently limited despite the expression of more than 600 E3 ligases in human cells. I will discuss our rationale and efforts in the discovery, DMPK properties and use of novel E3 ligands.     

This talk will describe a strategy leveraging our internal file through a binding-first Hit ID approach to identify ligands for a new E3 ligase. Potency optimization was achieved using structure-based drug design (SBDD), resulting in the development of novel chemical tools to explore target biology.

We have developed a set of single amino acid-based PROTACs for target destruction by the N-end rule pathway. The modular design described offers unique advantages, including high potency, degradation rate modulation with different amino acids, and smaller molecular size with shortest degradation sequences. We demonstrate the utility and efficacy of these PROTACs, furthering expanding the repertoire of limited degrons and pathways available for PROTACs in the fight against various cancers.

The development of proximity-induced degraders still poses several challenges, including their relatively low cell-permeability, as well as high degree of conformational flexibility due to the presence of flexible linker elements. I will present our strategy to identify conformationally constrained macrocyclic degraders. I will further highlight our characterization cascade comprising ternary complex stabilization, as well as property-based optimizations to obtain in vivo bioactive compounds.

QuEEN™ is a proprietary molecular glue discovery engine generating therapeutics that selectively degrade disease-causing proteins. I will discuss Monte Rosa’s approach to accelerate molecular glue degrader discovery and validation  and the development of potent and selective molecular glue degraders.

In collaboration with Georg Winter’s lab, we investigated and structurally resolved the mode of action of bifunctional BRD4 degraders (IBG1-4) and showed that—instead of connecting target and ligase in trans as PROTACs do—they simultaneously engage two adjacent domains of the target protein in cis. This conformational change glues BRD4 to the E3 ligases DCAF11 or DCAF16, leveraging intrinsic but non-functional target-ligase affinities. Structural insights guided the rational design of improved degraders of low picomolar potency. We thus introduce a new modality in targeted protein degradation, termed intramolecular bivalent glues (IBGs), which work by bridging protein domains to enhance surface complementarity with E3 ligases for productive ubiquitination and degradation.

Covalency have been largely adopted as an accepted strategy in the development of chemical probes and drugs for challenging targets. It has also gained traction in the targeted degradation field, mostly in targeting the E3 ligase or effector. Here I will share our results on using reversible covalent chemistry to bind the PROTAC target, as well as recent progress in using Covalent Ligand Directed Release chemistry for targeted degradation.