This talk will discuss ubiquitin-proteosome system vs. autophagy-lysosome system; the POC studies of proximity-induced, autophagy-dependent degradation; and the potential of autophagy-based, targeted degradation.

Aggregates of neurodegeneration-associated hallmark proteins are causative agents of neuronal proteotoxicity, leading to progressive cell death and brain tissue deterioration. Targeted protein degradation represents an exciting and alternative approach to move beyond traditional inhibitors that have been limited to treating symptoms in neurodegeneration, and fundamentally eliminate the causative pathological agents. The AUTOphagy-TArgeting Chimera (AUTOTAC) TPD platform was used to selectively degrade pathological aggregates, and combat neurodegeneration-associated pathophysiology.

Progress and success in drug discovery are highly dependent on the availability of robust and quantitative assays that allow for the straightforward and reliable characterization of molecular interactions and target abundance. We have developed novel CoraFluor-based TR-FRET assay approaches that overcome existing limitations and facilitate the accurate profiling of molecular degraders and transcriptional regulators, including the facile quantification of endogenous protein levels, target affinity measurements, and characterization of ternary complexes.   

An important step in the development of drugs targeted for central nervous system activity involves the accurate determination of the extent of drug exposure to the brain.  We have recently evaluated the TRANSIL Brain Absorption assay, a high-throughput matrix-free method that measures the affinity of drugs to porcine brain membranes to estimate their binding to brain tissue and have correlated the unbound brain exposure to pharmacodynamic (PD) effect.

Blocking the signaling activity of Interleukin-1 receptor associated kinase 4 (IRAK4) represents an attractive target for the treatment of autoimmune diseases. The signaling activity of IRAK4 is dependent both on its kinase activity and  scaffolding functions, and thus degradation of IRAK4 represents a potentially superior approach to kinase inhibition. This presentation will detail the efforts that led to the identification of potent, selective and orally bioavailable degraders of IRAK4.  Included will be a discussion of the computational tools and approaches utilized for the discovery of KT-474 (SAR444656), a heterobifunctional degrader of IRAK4 that is currently entering Phase II clinical trials for the treatment of atopic dermatitis (AD) and hidradenitis suppurativa (HS). 

AML is a malignancy with limited treatment options and poor prognosis. CD33 represents a good target, with high expression in most AML blasts. Small-molecule GSPT1 degraders drive clinical response in AML patients, with tolerability challenges. We designed a CD33-targeted ADC with a GSPT1 degrader. ORM-6151 demonstrated robust activity against many AML models with high tolerability in healthy progenitors. ORM-6151 represents a novel therapeutic approach for the treatment of AML.

By phenotypic screening St. Jude’s proprietary molecular glue library across a range of pediatric cancer cell lines, we identified several degraders of CK1a. Through structure-guided optimization, we developed SJ3149, a potent and selective CK1a degrader. The crystal structure of the CK1a+CRBN+DDB1+SJ3149 complex provided rationale for the improved degradation via direct contacts between SJ3149 and CK1a. In a panel of 115 human cancer cell lines, SJ3149 displayed broad anti-proliferative activity.

BCL-X_L is a well-validated cancer target. However, the on-target and dose-limiting platelet toxicity induced by BCL-X_L inhibition prevents the clinical use of BCL-X_L inhibitors. In my presentation, firstly I will cover the discovery and development of the first-in-class platelet-sparing and tumor-selective BCL-X_L degrader DT2216. Next, I will share our recent preclinical data where we are using DT2216 in combination with different chemo- and targeted drugs with a goal of preventing resistance and developing safe and effective therapies.

PROTACs have generated considerable interest in drug discovery because of their potential to target so-called undruggable proteins. This talk will demonstrate our work using PROTACs as chemical probes for validating the degradation of the endoplasmic reticulum (ER) stress sensor IRE1α, which led to the development of the first degrader of the protein, as well as our discovery of catalytic degraders that effectively address kinase site mutations in EML4-ALK oncogenic fusions.

Transcription factors are known to bind to cereblon in the presence of molecular glues and some reports implicate interactions with multiple zinc fingers. We present biophysical and structural assessments of the minimal binding domains of IKZF2 and another transcription factor revealing that two zinc fingers interact with cereblon:glue complexes. In these examples, the binding modes are distinct and may have implications for the design of selective degraders.

IKZF2 (Helios) plays an important role in maintaining stability and function of regulatory T cells (Tregs). Proteovant applied a structure-guided drug discovery approach to identify an IKZF2 selective molecular glue degrader, PVTX-405. PVTX-405 shows selective degradation of IKZF2 in vitro and in vivo. PVTX-405 treatment reduces suppressive activity of human Treg cells ex vivo and delays growth of MC38 tumors in immune competent mice in vivo.

The Jian Jin Laboratory at Mount Sinai is a leader in discovering novel degraders targeting oncogenic proteins and developing new technologies for advancing the targeted protein degradation field. Our lab’s recent progress advancing the targeted protein degradation, including TF-PROTAC, Bridged PROTAC, Folate-caged PROTAC, opto-PROTAC, and KEAP1-recruiting PROTAC technologies will be presented.

STAT (signal transducer and activator of transcription) proteins are a family of transcription factors that mediate signal transduction downstream of cytokine and growth factor receptors. Hyperactivation of STAT3 and STAT5 has been linked to cancer cell proliferation, survival, stemness, and immune evasion, making them attractive targets for cancer therapy. STATs have been difficult to target by traditional small-molecule inhibitors. Employing the PROTAC technology, we have developed highly selective and potent STAT3 or STAT5 degraders with strong anti-tumor activities in hematologic cancer models.