Biology subjects

Taherbhoy, A. M.

Publications and source records attributed to Taherbhoy, A. M..

3 recordsLinked to original sources

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

Structural and functional basis of PU.1-BAF interaction enables targeting of lineage-specific transcription

Chromatin remodeling complexes like BAF finely regulate transcriptional programs by working in concert with transcription factors. However, evidence is lacking as to whether TFs interact directly with BAF and if so, what the mechanistic and structural principles governing these critical interactions are. Here, we establish direct engagement between a crucial and therapeutically relevant full-length human TF, PU.1 (SPI1), and BAF. Within this 1MDa+ complex, we precisely map the binding site of PU.1 to a YEATS-like domain on BAF60A and elucidate the structure of the PU.1-BAF60A complex. This work reveals that upon binding to BAF, a disordered region within the TF adopts a helical conformation, and that disruption of this functionally critical interface via knockdown abrogates the ability of PU.1 to rescue cell viability. To explore the druggability of TF-BAF protein-protein interactions (PPIs), we conducted a high-throughput screen that identified small molecules capable of disrupting the PU.1-BAF60A PPI by binding to BAF60A. Co-crystal structures reveal distinct compound binding modes that converge on a critical PU.1-BAF60A interaction hotspot. These findings define, for the first time, the structural interface between a human TF and a chromatin remodeling complex and establish a platform that enables the targeting of these interactions, a novel mechanism in cancer therapeutics.

biochemistry↗

bioRxiv2023

Hijacking the transcriptional activation potential of the BAF complex via Induced Proximity

The BAF (Brg/Brahma-associated factors) complex, also referred to as the mammalian Switch/Sucrose-Nonfermentable (mSWI/SNF) chromatin remodeling complex, plays a pivotal role in epigenetically regulating diverse transcriptional programs. BAFs chromatin remodeling activity, which enhances accessibility to transcriptional machinery, is critical for gene regulation. Recent studies have demonstrated that redirecting BAF complexes to bivalent promoters can alter the local epigenetic landscape, creating a permissive environment for transcription. As such, we hypothesize that redirecting BAF to "turn on" therapeutically relevant genes offers a potential approach for disease treatment. Using rapamycin as a chemical inducer of proximity (CIP) via CRISPR/Cas9 and FKBP/FRB dimerization, we redirected BAF complexes to the promoter of fetal hemoglobin (HBG), a therapeutic target for beta-globinopathies like sickle cell anemia and beta-thalassemia. This resulted in changes to the local chromatin and epigenetic landscapes, and increased HBG1 expression. Having confirmed BAFs ability to activate gene expression, we then performed a genome-wide CRISPR activation drop-out screen to identify genes that when activated by BAF, suppress cellular proliferation. In addition to known tumor suppressors, our screen identified a number of genes with the ability to inhibit cell proliferation when activated by BAF. Collectively, our findings highlight the potential for harnessing the BAFs intrinsic transcriptional activation capabilities for therapeutic purposes and lays the foundation for the potential development of therapeutics that function via induced proximity.

cell biology↗