Biology subjects

Weiss, D. R.

Publications and source records attributed to Weiss, D. R..

4 recordsLinked to original sources

bioRxiv2026

Bexobrutideg: A Selective, Catalytic Degrader of Bruton's Tyrosine Kinase Overcomes Inhibitor Resistance and Suppresses Autoantibody-Mediated Disease

Brutons tyrosine kinase (BTK) transduces B-cell receptor (BCR), Toll-like receptor (TLR), and Fc receptor (FcR) signaling, and overactivation of these pathways drives B-cell malignancies and antibody-mediated autoimmune disease. Small molecule inhibitors block the enzymatic functions of BTK, but this inhibition is undermined by resistance mutations, several of which abolish BTKs kinase activity yet promote oncogenic signaling through BTK scaffolding functions. We report the discovery and characterization of bexobrutideg (NX-5948), a heterobifunctional degrader that recruits cereblon (CRBN) to selectively degrade BTK while sparing molecular glue neosubstrates. We demonstrate that bexobrutideg acts catalytically, degrading thousands of copies of BTK per molecule per hour, and this event-driven pharmacology renders it resilient to mutations that confer resistance to both covalent- and noncovalent-inhibitors. Bexobrutideg is orally bioavailable, driving deep and durable BTK degradation across species. Bexobrutideg demonstrates strong efficacy in wild-type and ibrutinib-resistant lymphoma models and robustly suppresses pathway activation in models of autoimmune disease.

cancer biology↗

bioRxiv2026

Discovery and characterization of small molecule inhibitors of CBL-B that act as intramolecular glue to enhance T-cell anti-tumor activity

CBL-B is a RING-type E3 ubiquitin ligase that acts as a critical negative regulator of T-cell activation. It promotes T-cell anergy and suppresses immune responses through ubiquitin-mediated control of signaling proteins at the immunological synapse. T cells deficient in CBL-B activity lose their dependence on CD28 co-stimulation, exhibit heightened activation and increased cytokine production, and fail to re-establish anergy. In addition, mice deficient in CBL-B activity reject tumors. Together, this cellular mechanism and in vivo phenotype suggest inhibition of CBL-B may be a viable immuno-oncology therapeutic strategy. Here, we report the rational design and execution of a high-throughput screen (HTS) to identify small molecule inhibitors of CBL-B. This campaign led to the discovery of a scaffold that inhibits CBL-B E3 ligase activity with micromolar potency. Structural characterization revealed an intramolecular glue mechanism, in which the compound stabilizes the closed state of CBL-B, preventing phosphorylation of a tyrosine residue that is critical for activation and E2 binding. Iterative structure-activity optimization yielded compounds with nanomolar activity that enhanced T-cell activation and cytokine secretion in primary human T cells and suppressed tumor growth in a syngeneic colorectal mouse model. Together, these studies validate the biological rationale for pharmacological CBL-B inhibition and enabled the de novo discovery of intramolecular CBL-B glue inhibitors. This work culminated in the identification of NX-1607, a first-in-class oral CBL-B inhibitor now in clinical development for cancer immunotherapy.

immunology↗

bioRxiv2025

Balanced Permeability Index is a Strong Predictor of Intestinal Absorption and Oral Bioavailability for Heterobifunctional Ligand-Directed Degraders

Ligand-directed degraders (LDDs) are heterobifunctional molecules that degrade proteins by engaging the ubiquitin-protein ligase (E3) system. LDDs consist of a target-engaging moiety, an E3 ligase-binding moiety and a bridging linker. Due to their size and physicochemical complexity these molecules do not adhere to well-established rules of lead optimization. The optimization of passive permeability remains a key challenge to develop orally bioavailable LDDs. To overcome this challenge, in this study we demonstrate that the Balanced Permeability Index (BPI)--a new metric that combines size, polarity and lipophilicity--is highly predictive of oral bioavailability for LDDs. Here, we introduce an additional parameter--called smallest maximum intramo-lecular distance (SMID)--to the original BPI index to account for cross sectional area of LDDs, termed BPILDD. With this new parameter, BPILDD can differentiate oral bioavailability of LDDs in our dataset more effectively than polarity, lipophilicity, or size separately. In addition, BPILDD is also more effective at identifying orally bioavailable LDDs than some in vitro measurements of cell permeability that traditionally inform bioavailability. This finding opens the possibility of employing BPILDD for the design and optimization of orally bioavailable LDDs to improve their drug metabolism and pharmacokinetics properties.

pharmacology and toxicology↗

bioRxiv2023

Balanced Permeability Index: a multi-parameter index for improved in-vitro permeability

The optimization of passive permeability is a key objective for orally available small molecule drug candidates. For drugs targeting the central nervous system (CNS), minimizing P-gp mediated efflux is an additional important target for optimization. The physicochemical properties most strongly associated with high passive permeability and lower P-gp efflux are size, polarity and lipophilicity. In this study, a new metric called the Balanced Permeability Index (BPI) was developed that combines these three properties. The BPI was found to be more effective than any single property in classifying molecules based on their permeability and efflux across a diverse range of chemicals and assays. The BPI can also be used to guide optimization in non-traditional small molecule modalities, such as protein degraders, which often lie outside of traditional small molecule space. BPI is easy to understand, allowing researchers to make decisions about which properties to prioritize during the drug development process.

bioinformatics↗