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Selected applications of TRIFECTA

Below is a partial list of our capabilities for which we have POC. The biological E3 ligases for the candidates mentioned below are either known or can be copurified from our samples for designing TPD solutions:

• Target identification and protein degradation in Inflammation, Immunity, Neurodegeneration, & Oncology.

  • We applied our PINTAC assay to identify a 'degrome' of over 250 proteins involved in apoptosis. Each of the apoptotic pathways known in humans is represented in this degrome by several to as many as 30 or more proteins. The degrome includes many ligandable proteins and subgrouped into cohorts for further delineating the roles of RIPK1 and RIPK2.
  • The PINTAC is being optimized for mapping the fine structure of the degrome, identifying candidates which are part of, or extend NF-KB, JNK, Akt1, Bcl2, caspase, or Traf pathways, calcium homeostasis mechanisms, or exhibit crosstalk.
  • A cohort of 35 degrome proteins could not be associated with any apoptosis pathways, and are being investigated further.
  • Included in the degrome are separate cohorts each of proteins with roles in autophagy, mitophagy, ferroptosis, and necroptosis.
  • Vistara seeks a collaboration for screening for small molecule inhibitors of degrome structure or individual proteins, including RIPK1, RIPK2, and XIAP. The collaboration may also include characterizing the degrome proteins, annotating the proteins with apoptotic pathways, and co-developing drug candidates, including PROTACs, molecular glue, or PINTAC.

• Target identification and TPD in Neurodegeneration.

  • A degrome of 128 proteins mostly involved in Stress Granule metabolism was identified with a second PINTAC. Many of the proteins are clinical candidates in Alzheimer's, Amyotropic Lateral Sclerosis (ALS), or Fronto-Temporal Dementia (FTD).
  • The degrome is being characterized by optimizing the PINTAC sequence to include known mutations in these diseases, some of which are causative. We are mapping the proteins into cellular substructures and colocalizing with the E3 ligase involved.
  • Vistara seeks a collaboration for discovery of small molecules by screening against the 'degrome' proteins as a network or against individual candidate proteins. The identified ligands may be employed in PROTAC constructs or molecular glues. The collaboration may also utilize cells engineered with PINTACS with validated degrome proteins for small molecule discovery.

• Targeting Protein Kinases with small molecule, degraders, and/or PINTACs.

  • We have identified more than 100 protein kinases in an active state of proteostasis. We are identifying the biological E3 ligases for some candidates for screening for small molecules for use in TPD vehicles, or which may phenotypically alter proteostasis by modulating protein networks.
  • Vistara seeks a collaboration for characterizing candidate protein kinases in Oncology, and developing TPD solutions.

• A TPD solution for Estrogen Receptor (ESR1)

  • We have detected ESR1 with UBQuest and are co-purifying the biological E3 ligase responsible, as well as localizing the E3L recognition site in ESR1.
  • Selectively inactivating function of ESR1 or its biological E3L with PINTACs will shed light on the roles of degrome partners and organelle -specific function of ESR1. Our PINTACs can be designed to selectively knock-out ESR1 either at the plasma membrane, in the cytosol, or nucleus. The knowledge gained from understanding the sensitivity of ESR1 degradation to spatial or temporal signaling mechanisms as well as cell type specificity will help select the best approaches for TPD. The degrome signature and biomarker profiles from above studies will guide identification of small molecules.
  • The PINTACs or degrome signatures will also be employed for screening for adjacent opportunities for TPD therapeutics of ESR1.

• Platform solutions and other candidates for TPD

  • We can target many additional E3 ligases with PINTACs for identifying their substrate repertoire and select candidates for TPD applications.
  • Many clinical candidate proteins are currently available for functional disruption via polyubiquitination and creation of engineered cells for drug discovery research.