Cardozo, M. | bioRxiv Science

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↗

bioRxiv2019

Attraction of Triatoma infestans (Klug) to adhesive yeast-baited trap under laboratory conditions

Existing methods to detect domestic triatomines have low sensitivity. As early house infestation detection is epidemiologically important, the exploration of better methods is required. Hence, we measured the attractiveness of a yeast-baited trap to adults and nymphs of Triatoma infestans, under laboratory conditions.\n\nThe assays were conducted in an experimental arena, with an experimental and a control traps placed at opposite sides and one refuge in the center area. Insects where released and the number of triatomines in the yeast and control traps were counted, after 3, 6 and 24 hours of the beginning of the experiment. We use generalized linear models within a multimodel inference approach to model the number of insects in the trap, using insect age classes, time after assay initiation and date of the experiment as predictors.\n\nOur results show that the attraction to CO2 depends upon the life stage of the insects. During the 24 hours of experiment a constant number of adults were attracted to the yeast trap, while nymphs show attraction only up to the first three hours after the initiation of CO2 liberation. Undoubtedly, the orientation response to chemical cues deserves further studies to be fully understood.

ecology↗