公开(公告)号：US12048679B2

公开(公告)日：2024-07-30

申请号：US17716645

申请日：2022-04-08

Applicant: University of Southern California

Inventor： Keigo Machida

IPC: A61K31/191 ,  C12Q1/6886 ,  G01N33/53

CPC classification number: A61K31/191 ,  C12Q1/6886 ,  C12Q2600/136 ,  C12Q2600/158

Abstract: The molecular mechanism of the function of TBC1D15 in NOTCH activation and stabilization is associated with maintenance and expansion of tumor-initiating stem-like cells (TICs). We herein demonstrate that TBC1D15 preferentially binds an NUMB isoform and NOTCH1-PEST domain and stabilizes NOTCH1 protein. This interaction enhances phosphorylation of NUMB, taking it away from NUMB-mediated ubiquitin degradation of NOTCH. Thus, TBC1D15 acts as a switch to augment NOTCH signaling in TICs. We also have identified inhibitors of TBC1D15 such as latanoprost acid and a salt thereof, which blocks the NOTCH-TBC1D15 interaction and selectively kills CD133-positive TICs, resulting in a reduction in the tumor size in a patient-derived, hepatocellular carcinoma xenograft model.